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Open AccessArticle

In-silico Leishmania Target Selectivity of Antiparasitic Terpenoids

1
Department of Chemistry and Biochemistry, Jackson State University, Jackson, MS 39217, USA
2
Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA
*
Author to whom correspondence should be addressed.
Molecules 2013, 18(7), 7761-7847; https://doi.org/10.3390/molecules18077761
Received: 20 May 2013 / Revised: 23 June 2013 / Accepted: 26 June 2013 / Published: 3 July 2013
(This article belongs to the Special Issue Plant Natural Products against Human Parasites)

Abstract

Neglected Tropical Diseases (NTDs), like leishmaniasis, are major causes of mortality in resource-limited countries. The mortality associated with these diseases is largely due to fragile healthcare systems, lack of access to medicines, and resistance by the parasites to the few available drugs. Many antiparasitic plant-derived isoprenoids have been reported, and many of them have good in vitro activity against various forms of Leishmania spp. In this work, potential Leishmania biochemical targets of antiparasitic isoprenoids were studied in silico. Antiparasitic monoterpenoids selectively docked to L. infantum nicotinamidase, L. major uridine diphosphate-glucose pyrophosphorylase and methionyl t-RNA synthetase. The two protein targets selectively targeted by germacranolide sesquiterpenoids were L. major methionyl t-RNA synthetase and dihydroorotate dehydrogenase. Diterpenoids generally favored docking to L. mexicana glycerol-3-phosphate dehydrogenase. Limonoids also showed some selectivity for L. mexicana glycerol-3-phosphate dehydrogenase and L. major dihydroorotate dehydrogenase while withanolides docked more selectively with L. major uridine diphosphate-glucose pyrophosphorylase. The selectivity of the different classes of antiparasitic compounds for the protein targets considered in this work can be explored in fragment- and/or structure-based drug design towards the development of leads for new antileishmanial drugs.
Keywords: antileishmanial activity; terpenoids; drug targets; docking; Leishmania antileishmanial activity; terpenoids; drug targets; docking; Leishmania

1. Introduction

Several closely-related protozoan parasites in the genus Leishmania are etiological agents for a number of clinical forms of leishmaniasis. These clinical forms of leishmaniasis are characterized as either cutaneous, diffuse cutaneous, disseminated cutaneous, mucocutaneous, visceral or post-kala-azar dermal. Species causing this protozoan disease have been reported in several tropical and Neotropical regions including Africa, the Americas, Eastern Europe, central and western Asia, the Indian subcontinent as well as in Australia. There are over 350 million people at risk of infection in Leishmania-endemic regions. There are several treatment options for leishmaniasis, although the effectiveness of the available drugs depends on which clinical form is being treated, and also on the specific geographical location. For a review of the current treatment options please see reference [1]. There remains a need for better chemotherapy for cutaneous, visceral and post-kala-azar dermal leishmaniasis, as well as, Leishmania-HIV co-infection.
Current chemotherapy of visceral and cutanoeus leishmaniasis includes miltefosine, a compound that has been demonstrated to inhibit P13K/Akt signaling pathway, and fluconazole, a sterol 14α-demethylase inhibitor. In addition to currently targeted Leishmania proteins, several other proteins have also been identified, or suggested as potential drug targets in Leishmania [2,3,4,5]. Most of these targets include enzymes that are critical to the metabolism of glucose, sterols, nucleotides and glycosylphosphatidylinositol, as well as enzymes important for the maintenance of trypanothione and polyamine levels. Many of these proteins have been shown to be important to the survival of the parasites. Other targets include cyclin-dependent- and mitogen-activated protein kinases, topoisomerases and cathepsin-like proteases.
Some of the enzymes that are involved in glucose metabolism and are potential drug targets in some species of Leishmania include pyruvate kinase (PYK) [6,7], phosphoglucose isomerase (PGI) [8,9], uridine diphosphate-glucose pyrophosphorylase (UGPase) [10], glyceraldehyde-3-phosphate dehydrogenase (GAPDH) [11,12,13], glycerol-3-phosphate dehydrogenase (GPDH) [14,15], triosephosphate isomerase (TIM) [16,17,18], thiol-dependent reductase I (TDR1) [19] and phosphomannomutase (PMM). TDR1 is involved in the regulation of the terminal steps of glycolysis and the enzyme fortuitously catalyzes the activation of antiparasitic antimonial prodrugs while PMM catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate, which is essential for the biosynthesis of glycoconjugates, and it has been suggested to be a potential drug target [20]. The enzyme that catalyzes the trypanothione-coupled conversion of methylglyoxal, a toxic byproduct of glycolysis, to lactate in Leishmania, glyoxalase II (GLO2), has also been suggested as a drug target [21,22] although modeling studies of the enzyme have suggested that inhibition of glyoxalase II will have little effect on toxic glyoxal build up in the cell [23]. In addition to these, the cysteine protease, cathepsin B (CatB) [24,25], as well as oligopeptidase B (OPB) [26,27,28] are also being investigated as potential drug targets. A number of proteins involved in nucleoside and nucleotide metabolism in Leishmania have also been investigated as druggable targets. These includes dihydroorotate dehydrogenase (DHODH), an enzyme involved in the de novo synthesis of pyrimidine [29,30], deoxyuridine triphosphate nucleotidohydrolase (dUTPase), an enzyme involved in controlling intracellular dUTP levels [31,32,33], nicotinamidase (PnC1), an essential enzyme for the production of NAD+ [34], nucleoside hydrolase (NH) [35,36,37], nuceloside diphosphate kinase b (NDKb) [38] as well as phosphodiesterase 1 (PDE1) [39,40,41] and pteridine reductase 1 (PTR1) [42,43,44,45]. Also, proteins involved in co-/post-translational protein processing like N-myristoyltransferase (NMT) [46,47,48] and cyclophilins (Cyp) [49,50] have being actively investigated as antileishmanial drug targets as well as charged-tRNA synthesizing enzymes, methionyl-tRNA synthetase [51] and tyrosyl-tRNA synthetase [52].
Numerous phytochemical agents have exhibited either in vitro or in vivo antileishmanial activity [5,53,54,55,56,57,58,59,60,61]. While the activities of many of these compounds are notable, what is generally unknown are the biochemical targets of these agents. In this study, we have carried out a molecular docking analysis of known antiparasitic plant-derived isoprenoids with established drug targets with known structures available from the Protein Data Bank.
Figure 1. Monoterpenoids examined in this study.
Figure 1. Monoterpenoids examined in this study.
Molecules 18 07761 g001
Table 1. MolDock docking energies (kJ/mol) of monoterpenoids with Leishmania major protein targets.
Table 1. MolDock docking energies (kJ/mol) of monoterpenoids with Leishmania major protein targets.
MonoterpenoidsLmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLmajNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
δ-3-Carene−43.8−63.0−50.0−56.3−51.0−52.9−62.7−56.9−54.9−60.8−63.2−65.1
Camphor−43.2−61.3−39.2−52.4−50.4−50.0−49.1−58.1−43.6−52.0−44.6−60.9
Carvacrol−46.5−64.8−58.9−61.9−52.7−69.9−66.6−62.6−62.1−70.9−66.7−66.2
(S)-Carvone−46.7−68.9−56.0−63.6−53.2−55.8−56.0−63.6−56.6−69.2−61.5−66.5
1,8-Cineole−37.1−57.6−37.8−50.6−43.5−45.7−42.5−53.6−39.7−46.8−45.4−59.6
p-Cymene−40.8−55.7−54.6−54.8−51.4−63.0−57.6−58.1−56.5−61.9−63.6−60.7
Geranial−52.8−69.0−67.3−77.1−65.8−75.6−63.8−66.7−72.8−76.8−73.7−76.9
Geraniol−55.9−69.7−68.9−73.5−67.5-72.8−68.0−65.1−70.2−76.5−72.1−74.1
Isopulegol−46.3−64.8−51.1−59.0−55.4−63.6−54.7−57.0−53.8−61.0−65.0−62.6
(R)-Limonene−46.1−61.6−49.6−59.5−47.5−52.4−56.4−57.6−57.2−63.4−58.4−65.6
(S)-Limonene−44.3−58.7−56.4−56.2−50.0−65.9−59.5−58.6−56.3−64.3−66.0−62.0
Limonene oxide−44.1−65.2−48.2−57.7−52.5−52.5−59.6−59.0−50.1−59.0−52.0−64.8
Linalool−52.3−67.4−63.9−70.1−62.0−71.0−63.2−65.5−65.7−73.7−72.5−71.9
Myrtenal−47.1−64.3−45.7−56.5−48.8−51.5−60.8−61.8−51.7−57.3−55.7−66.2
Neral−49.6−72.2−68.3−76.6−68.0−75.2−64.6-67.3−71.8−75.3−71.0−75.6
Perilla alcohol−49.0−63.1−58.2−60.9−52.3−72.9−68.1−64.0−63.5−73.6−72.9−63.5
(R)-α-Phellandrene−41.7−61.6−53.2−59.8−51.0−53.8−56.4−55.9−59.2−66.7−60.8−66.4
(S)-α-Phellandrene−42.2−60.3−54.5−57.8−51.9−65.1−58.6−58.3−55.0−65.3−64.7−63.6
α-Pinene−40.0−54.9−39.3−52.0−45.1−44.9−53.4−53.4−42.0−53.4−49.4−60.6
β-Pinene−39.6−55.5−39.8−52.6−47.0−45.3−52.9−53.7−41.3−54.3−47.5−60.4
(R)-Piperitone−45.9−63.0−54.9−60.2−51.9−67.0−60.2−63.1−62.0−63.8−65.0−67.9
(S)-Piperitone−46.8−67.4−54.6−61.2−50.8−60.8−61.2−62.3−59.7−65.6−64.9−68.0
Sabinene−43.7−63.4−54.6−63.3−51.4−55.8−58.9−57.5−58.4−66.5−62.0−67.0
γ-Terpinene−41.1−57.4−56.0−56.0−52.4−65.5−58.8−59.7−57.5−63.5−65.5−62.0
Terpinen-4-ol−47.5−62.5−57.4−59.7−53.2−60.8−58.9−61.0−61.7−66.9−69.8−64.4
Terpinolene−46.2−59.8−52.6−55.3−49.1−58.8−55.3−58.5−57.0−62.8−62.3−61.2
α-Thujone−48.4−73.0−55.8−62.2−51.7−59.0−58.6−64.3−63.5−73.8−62.1−67.5
β-Thujone−47.6−69.7−58.2−60.2−56.9−59.7−62.8−65.0−62.3−71.0−62.5−67.9
Thymol−45.8−61.7−55.7−60.9−52.3−68.7−59.2−64.2−62.9−65.6−69.5−63.8
Verbenone−41.4−62.0−44.3−57.5−49.4−51.0−48.7−58.2−47.0−53.0−52.7−63.2
Table 2. MolDock docking energies (kJ/mol) of monoterpenoids with Leishmania donovani and L. mexicana protein targets.
Table 2. MolDock docking energies (kJ/mol) of monoterpenoids with Leishmania donovani and L. mexicana protein targets.
MonoterpenoidsLdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
Site 1Site 2Site 3
δ-3-Carene−50.9−56.1−59.4−49.5−53.7−59.1−43.5−51.8−58.9−50.8−59.4−58.0
Camphor−42.7−48.0−62.2−47.6−44.4−58.8−40.9−50.4−50.2−45.7−55.1−45.9
Carvacrol−58.3−63.8−57.9−64.9−56.0−61.2−48.6−57.9−63.9−53.4−65.5−56.3
(S)-Carvone−54.0−65.6−60.3−59.7−49.6−61.2−49.5−58.3−62.4−55.5−62.9−54.1
1,8-Cineole−36.3−46.8−53.6−38.0−39.8−51.1−37.6−47.1−52.5−42.7−50.3−48.3
p-Cymene−51.7−54.5−51.4−54.7−48.4−56.1−50.2−52.9−58.0−53.4−60.4−55.2
Geranial−68.7−67.2−65.2−75.0−66.6−70.4−74.4−63.9−71.1−61.2−75.2−71.4
Geraniol−69.3−68.2−65.8−71.7−64.2−72.4−70.1−63.1−71.3−61.6−75.5−70.1
Isopulegol−52.9−61.1−57.6−65.2−57.9−60.9−44.9−57.6−63.1−55.3−59.3−59.4
(R)-Limonene−52.1−58.6−57.2−51.8−49.5−58.1−43.4−53.3−56.9−51.1−58.1−53.1
(S)-Limonene−54.5−57.2−50.5−62.3−51.9−58.7−43.5−55.3−61.3−54.8−62.2−56.9
Limonene oxide−46.2−58.4−63.9−33.4−54.1−61.1−44.3−53.9−58.3−52.2−61.2−57.6
Linalool−65.1−65.1−70.5−65.6−61.4−67.8−58.6−66.9−68.7−60.1−74.8−65.9
Myrtenal−47.7−59.2−60.1−36.7−49.1−60.2−45.0−52.6−57.7−50.4−55.8−53.6
Neral−64.4−69.2−70.5−71.7−66.1−72.9−58.7−63.2−71.8−65.2−74.2−65.5
Perilla alcohol−58.7−65.2−57.5−71.0−60.3−63.1−50.4−57.7−67.0−57.8−68.7−60.7
(R)-α-Phellandrene−52.8−58.6−58.9−54.9−53.6−57.0−52.9−51.0−60.9−50.9−59.7−55.8
(S)-α-Phellandrene−53.4−59.1−55.0−59.2−52.5−57.2−47.7−53.3−61.9−52.7−62.1−55.2
α-Pinene−40.5−52.5−56.2−37.5−43.7−53.0−39.9−47.1−50.7−42.8−49.6−46.4
β-Pinene−39.7−53.2−57.4−39.5−45.2−52.4−39.2−47.3−49.9−41.8−50.7−48.2
(R)-Piperitone−57.5−66.1−54.1−65.1−57.1−60.2−50.4−58.0−62.7−54.8−61.9−58.4
(S)-Piperitone−55.3−63.2−64.2−59.3−53.8−61.2−46.7−57.4−63.8−56.1−62.2−56.4
Sabinene−49.3−59.0−57.9−59.4−50.9−59.9−46.0−52.1−61.0−51.6−61.2−55.8
γ-Terpinene−53.1−56.2−54.0−59.5−50.6−57.9−49.2−54.0−60.4−55.7−62.2−56.8
Terpinen-4-ol−52.4−63.8−55.1−64.6−51.4−61.7−51.8−56.9−64.5−56.9−65.6−58.7
Terpinolene−54.1−57.8−52.6−57.7−48.0−57.2−45.3−51.9−58.9−51.3−58.9−54.7
α-Thujone−51.3−63.8−63.6−53.2−56.1−65.0−49.8−56.6−65.2−54.2−62.2−57.7
β-Thujone−56.3−61.6−60.7−58.1−53.2−65.6−48.2−58.0−65.1−54.7−61.0−59.9
Thymol−55.8−61.3−54.5−64.1−52.1−62.3−47.2−56.6−65.2−56.3−61.7−57.1
Verbenone−40.9−58.0−61.6−45.4−48.1−59.6−42.4−52.2−56.9−49.2−58.0−48.9
Table 3. MolDock docking energies (kJ/mol) of monoterpenoids with Leishmania infantum protein targets.
Table 3. MolDock docking energies (kJ/mol) of monoterpenoids with Leishmania infantum protein targets.
MonoterpenoidsLinfCYP51LinfGLO2LinfPnC1LinfTDR1LinfTR
δ-3-Carene−50.4−48.0−66.1−45.9−56.3
Camphor−46.1−37.8−56.8−43.8−52.1
Carvacrol−59.5−53.8−71.0−53.5−60.9
(S)-Carvone−54.9−47.9−73.6−52.1−57.6
1,8-Cineole−43.3−34.9−54.4−39.5−50.6
p-Cymene−53.2−52.1−64.1−49.6−57.8
Geranial−63.0−61.7−75.0−64.3−70.1
Geraniol−64.5−59.1−74.8−64.2−69.1
Isopulegol−50.8−49.6−67.6−49.8−58.6
(R)-Limonene−51.6−51.4−68.8−48.4−54.0
(S)-Limonene−53.0−52.7−65.2−49.1−60.0
Limonene oxide−51.6−46.6−64.8−45.4−54.0
Linalool−61.6−56.1−72.7−62.2−66.1
Myrtenal−48.7−45.2−63.2−47.6−54.1
Neral−60.7−57.1−76.4−61.4−68.1
Perilla alcohol−61.9−60.0−69.3−57.8−65.5
(R)-α-Phellandrene−51.1−50.9−68.1−48.4−56.1
(S)-α-Phellandrene−53.9−51.2−66.3−50.6−59.4
α-Pinene−42.4−38.4−56.9−41.0−47.3
β-Pinene−43.0−37.5−56.9−41.6−48.3
(R)-Piperitone−54.9−50.2−70.9−51.3−62.8
(S)-Piperitone−54.2−51.6−73.0−54.2−60.3
Sabinene−52.9−53.8−68.2−54.4−58.8
γ-Terpinene−54.8−53.0−65.8−49.7−59.2
Terpinen-4-ol−53.2−51.3−69.4−50.4−63.3
Terpinolene−52.4−51.3−67.6−49.6−59.2
α-Thujone−53.8−53.9−74.5−54.0−60.4
β-Thujone−54.5−50.8−69.4−52.0−64.7
Thymol−60.2−53.5−71.5−52.9−59.6
Verbenone−50.2−42.2−63.0−48.0−50.5

2. Results and Discussion

2.1. Monoterpenoid Docking

The structures of the monoterpenoids examined in this study are shown in Figure 1, while the corresponding docking energies are summarized in Table 1, Table 2 and Table 3. The overall strongest docking monoterpenoid ligands were the acyclic geranial, geraniol, and neral, probably owing to their flexibility. These ligands, however, did not show docking selectivity to any of the Leishmania protein targets, but rather docked strongly to most of the proteins investigated. The protein targets that showed predominantly strong docking by monoterpenoids were L. major uridine diphosphate-glucose pyrophosphorylase (LmajUGPase), L. major methionyl t-RNA synthetase (LmajMetRS), and L. infantum nicotinamidase (LinfPnC1). Geranial had a docking energy of −76.9 kJ/mol with LmajUGPase, comparable in docking energy with several other proteins. Both enantiomers of piperitone showed significantly stronger docking to Lmaj UGPase (−68.0 kJ/mol) than the other targets, suggesting selectivity for that protein. Geranial was also the strongest docking ligand with LmajMetRS (−76.8 kJ/mol), but perilla alcohol (−73.6 kJ/mol) was selective for that protein target. Carvone, piperitone, and α-thujone showed significantly selective docking to LinfPnC1 (docking energies less than −73 kJ/mol). Interestingly, although the monoterpenoids showed a docking propensity for LinfPnC1, higher terpenoids (sesquiterpenoids, diterpenoids, and triterpenoids) showed very little inclination to dock to this protein, generally with positive docking energies (see below).
Monoterpenoids represents a very small percentage of terpene-derived compounds that have been reported to have antileishmanial activity, and the docking energies of monoterpenoids were generally weaker than those obtained for limonoids, withanolides, triterpenoids, steroids and diterpenoids with these same targets (see below). Their docking energies were much higher than the energies obtained for the co-crystallized ligands of those protein targets. The higher docking energies of these compounds correlate with their small size (and molecular weight), and the minimal intermolecular interactions they are able to have with the protein targets. So, comparatively, it appears that monoterpenoids will not be prime leads for structure-based antileishmanial drug discovery. However, they may be useful in fragment-based drug discovery [62,63]. Additionally, several terpene-derived compounds are used in topical formulations. Therefore, those monoterpenoids that have antileishmanial activity and no reported toxicity at physiologically relevant concentration/dosage should be evaluated as possible components of topical polytherapy for leishmaniasis.

2.2. Sesquiterpenoid Docking

Sesquiterpenoids examined in this work are shown in Figure 2, Figure 3, Figure 4 and Figure 5; docking energies of sesquiterpenoids are summarized in Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12, Table 13, Table 14 and Table 15. The germacranolide sesquiterpenoids exhibited the overall strongest docking energies toward the Leishmania protein targets, with 16,17-dihydrobrachycalyxolide the strongest-docking germacranolide. This ligand showed docking selectivity toward LmajMetRS (docking energy = −152.9 kJ/mol) and L. mexicana phosphor-mannomutase (LmexPMM) (docking energy = −136.3 kJ/mol). The two proteins most selectively targeted by the germacranolides in terms of docking energies were LmajMetRS and L. major dihydroorotate dehydrogenase (LmajDHODH). Although most germacranolides did not dock with LinfPnC1, tatridin A did show docking selectivity for this protein target. Based on molecular weight, the strongest-docking germacranolide was 4α,5β-epoxy-8-epi-inunolide, and this ligand showed docking selectivity toward both LmajMet RS and LmajDHODH.
Figure 2. Germacranolide sesquiterpenoids examined in this work.
Figure 2. Germacranolide sesquiterpenoids examined in this work.
Molecules 18 07761 g002
Figure 3. Guaianolide sesquiterpenoids examined in this work.
Figure 3. Guaianolide sesquiterpenoids examined in this work.
Molecules 18 07761 g003
Figure 4. Eudesmanolide sesquiterpenoids examined in this work.
Figure 4. Eudesmanolide sesquiterpenoids examined in this work.
Molecules 18 07761 g004
Figure 5. Miscellaneous sesquiterpenoids examined in this work.
Figure 5. Miscellaneous sesquiterpenoids examined in this work.
Molecules 18 07761 g005
Table 4. MolDock docking energies (kJ/mol) of germacranolide sesquiterpenoids with Leishmania major protein targets.
Table 4. MolDock docking energies (kJ/mol) of germacranolide sesquiterpenoids with Leishmania major protein targets.
GermacranolidesLmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLmajNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
8-Acetyl-13-O-ethylpiptocarphol−90.8−113.1−99.0−87.6−84.0−108.3−114.1−98.2−105.3−127.1−99.1−105.1
Centratherin−85.4−115.1−92.2−95.7−96.6−106.8−101.2−102.8−101.5−125.8−112.9−108.0
Costunolide−62.3−86.5−73.8−71.8−68.1−79.8−78.4−75.0−79.9−75.6−76.3−81.8
2-Deethoxy-2β-methoxyphantomolin−94.9−121.1−96.1−85.7−88.2−95.4−96.6−101.1−102.4−114.6−105.2−95.3
8,13-Diacetylpiptocarphol−92.2−115.1−105.5−93.4−88.9−106.7−100.2−102.6−107.3−131.5−99.6−110.6
16α,17-Dihydrobrachycalyxolide−100.1−129.1−112.5−117.3−111.0−121.5−100.2−122.8−105.0−152.9−117.7−115.7
11(13)-Dehydroivaxillin−78.0−108.3−78.6−80.6−81.5−84.4−91.4−81.9−89.1−101.9−88.3−95.7
11β,13-Dihydrotanachin−66.9−96.3−73.5−67.8−79.6−78.7−77.2−75.3−66.8−77.2−78.9−89.6
Elephantopin−86.7−114.6−98.8−90.3−91.5−105.0−97.8−106.8−103.9−119.3−105.0−105.7
11-epi-Ivaxillin−76.9−109.9−80.5−81.7−83.5−85.1−94.9−86.9−90.1−102.4−80.7−85.9
4,5α-Epoxy-6α-acetoxy-1(10)E,11(13)-germacradien-12,8α-olide−77.1−92.4−94.2−80.4−82.5−99.6−95.4−89.1−86.5−94.8−87.9−92.5
4α,5β-Epoxy-8-epi-inunolide−74.1−100.5−76.5−76.8−80.3−82.5−86.2−81.0−88.5−99.1−84.8−88.2
Eremantholide C−89.2−103.4−86.5−100.2−86.2−96.6−95.3−98.1−83.1−100.9−87.2−101.8
Eupatoriopicrin−83.7−107.8−106.2−99.2−104.9−114.5−111.1−105.7−100.3−120.7−97.3−102.0
Goyazensolide−73.5−107.0−90.0−97.6−93.1−108.4−101.1−107.7−98.2−116.4−110.9−107.4
Hanphyllin−71.2−91.5−73.8−76.9−77.7−80.8−79.5−76.3−80.7−85.7−84.5−84.4
8-(3'-Hydroxymethacryloxy)-hirsutinolide 13-acetate−94.0−107.3−106.8−105.6−104.4−107.8−105.0−110.7−109.6−134.9−105.1−108.6
Ineupatorolide A−83.1−117.3−90.0−92.4−91.0−98.7−100.4−97.2−112.8−119.4−112.1−105.9
Ivaxillin−76.6−104.2−79.3−78.3−75.2−83.2−90.6−82.6−83.4−98.1−82.8−88.3
Molephantin−80.8−105.0−87.4−80.0−87.4−101.6−87.9−99.0−94.7−106.0−99.3−91.9
Neurolenin B−86.0−116.4−88.0−100.0−88.7−95.6−77.3−103.0−86.7−99.8−90.3−99.5
Neurolenin C−82.7−116.3−93.0−94.4−86.2−102.1−89.6−95.8−102.6−112.6−99.0−117.6
Neurolenin D−90.5−111.1−95.9−99.2−92.4−97.5−87.9−101.4−94.6−104.7−90.7−100.6
Parthenolide−65.8−98.7−80.6−75.2−81.4−78.8−83.1−80.1−84.4−89.3−79.3−89.6
Tagitinin C−87.4−102.0−90.4−89.0−96.1−96.8−95.1−105.2−102.8−111.3−94.5−102.2
Tanachin−71.3−94.1−71.1−78.3−76.4−80.6−82.5−78.9−75.1−91.4−80.0−86.8
Tatridin A−74.1−96.6−69.7−75.7−76.3−80.7−88.6−78.4−89.8−91.2−80.8−90.7
8-Tigloylhirsutinolide 13-acetate−93.8−116.4−105.4−98.0−99.9−114.6−110.3−113.6−113.6−124.8−105.5−119.9
Vernolide D−97.8−124.5−110.9−106.3−121.8−117.9−112.4−118.3−114.4−128.1−111.8−121.5
Table 5. MolDock docking energies (kJ/mol) of germacranolide sesquiterpenoids with Leishmania donovani and L. mexicana protein targets.
Table 5. MolDock docking energies (kJ/mol) of germacranolide sesquiterpenoids with Leishmania donovani and L. mexicana protein targets.
GermacranolidesLdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
Site 1Site 2Site 2
8-Acetyl-13-O-ethylpiptocarphol−92.9−97.6−79.4−84.2−93.2−99.2−88.6−113.3−102.5−94.9−99.2−95.1
Centratherin−89.0−−88.7−86.0−90.9−82.2−126.6−87.5−108.9−100.3−96.0−107.5−100.6
Costunolide−78.9−80.5−61.1−65.8−63.5−80.6−64.5−76.0−84.8−73.8−87.1−77.6
2-Deethoxy-2β-methoxyphantomolin−101.6−88.0−80.7−87.6−88.7−110.2−87.4−110.3−103.1−85.8−105.8−79.2
8,13-Diacetylpiptocarphol−86.4−99.7−88.0−92.8−96.2−102.6−97.4−118.1−103.0−100.4−94.7−100.0
16α,17-Dihydrobrachycalyxolide−104.2−104.4−100.0−96.1−108.9−130.0−107.9−136.3−125.1−108.8−110.3−114.6
11(13)-Dehydroivaxillin−78.1−85.0−64.3−83.7−72.9−99.4−68.0−90.6−91.0−79.8−106.6−81.8
11β,13-Dihydrotanachin−73.4−77.2−52.3−75.2−69.6−81.9−67.2−79.1−82.3−74.9−78.1−66.1
Elephantopin−83.4−90.2−86.6−88.1−82.6−116.1−89.7−115.8−110.5−92.9−103.0−92.4
11-epi-Ivaxillin−77.0−84.8−66.5−88.4−74.1−96.3−66.4−88.9−93.2−79.4−106.9−78.0
4,5α-Epoxy-6α-acetoxy-1(10)E,11(13)-germacradien-12,8α-olide−77.0−90.7−66.4−82.3−73.0−98.9−79.5−91.7−97.8−88.0−88.3−81.5
4α,5β-Epoxy-8-epi-inunolide−73.3−85.8−76.9−78.8−67.6−90.7−62.3−86.8−87.8−75.2−95.4−78.6
Eremantholide C−87.6−98.8−86.4−76.2−77.4−114.2−79.9−103.2−102.0−104.2−85.1−94.2
Eupatoriopicrin−87.0−94.3−98.3−96.1−99.5−116.5−92.5−102.7−119.4−103.5−96.0−97.7
Goyazensolide−86.2−85.7−83.9-82.3−87.8−124.1−88.4−107.9−99.0−95.9−103.4−98.7
Hanphyllin−85.4−85.0−32.6−67.3−69.8−81.3−66.5−80.5−86.6−75.1−87.5−83.5
8-(3'-Hydroxymethacryloxy-hirsutinolide 13-acetate−98.6−98.4−80.0−98.5−88.4−113.9−96.1−117.6−112.4−101.4−110.7−103.4
Ineupatorolide A−97.4−95.2−94.2−86.5−72.5−102.4−82.2−99.7−100.1−91.2−100.4−104.6
Ivaxillin−73.9−84.9−74.6−78.3−77.9−90.4−68.4−91.3−93.5−77.9−105.0−80.7
Molephantin−87.9−94.5−36.3−89.4−79.4−92.9−78.8−96.6−106.8−88.8−99.8−99.9
Neurolenin B−88.1−82.6−66.6−76.5−77.7−98.4−80.1−110.7−103.3−92.0−100.4−85.9
Neurolenin C−93.6−89.8−49.0−94.7−86.5−94.4−79.3−106.0−95.0−89.9−91.6−95.2
Neurolenin D−94.8−78.1−77.6−95.3−87.1−94.1−80.8−111.4−97.7−89.1−92.4−92.0
Parthenolide−73.2−81.2−75.6−75.4−63.6−89.6−64.8−84.4−88.5−79.3−88.9−78.1
Tagitinin C−88.0−84.6−52.0−87.5−85.2−92.8-78.0−112.3−101.4−91.5−98.0−91.4
Tanachin−77.7−82.1−58.7−71.0−70.6−89.8−69.9−81.7−86.0−83.4−77.9−83.4
Tatridin A−84.7−84.5−67.6−72.8−59.3−85.7−61.6−83.8−83.5−81.2−89.7−76.9
8-Tigloylhirsutinolide 13-acetate−104.5−83.9−94.8−97.3−91.0−110.3−99.2−117.5−111.3−98.3−108.0−102.8
Vernolide D−107.5−94.3−89.6−102.3−94.8−120.3−96.8−125.4−117.4−113.7−99.8−109.1
Table 6. MolDock docking energies (kJ/mol) of germacranolide sesquiterpenoids with Leishmania infantum protein targets.
Table 6. MolDock docking energies (kJ/mol) of germacranolide sesquiterpenoids with Leishmania infantum protein targets.
GermacranolidesLinfCYP51LinfGLO2LinfPnC1LinfTDR1LinfTR
8-Acetyl-13-O-ethylpiptocarphol−100.4−89.8no dock−82.3−99.7
Centratherin−109.0−87.1no dock−88.5−104.9
Costunolide−74.4−63.6no dock−69.9−71.2
2-Deethoxy-2β-methoxyphantomolin−101.4−83.7no dock−83.2−95.3
8,13-Diacetylpiptocarphol−97.8−88.8no dock−91.7−101.6
16α,17-Dihydrobrachycalyxolide−126.4−108.8no dock−104.2−112.9
11(13)-Dehydroivaxillin−81.4−69.4−86.5−79.4−81.2
11β,13-Dihydrotanachin−73.7−63.2−86.6−72.2−76.3
Elephantopin−110.7−90.5no dock−92.2−104.4
11-epi-Ivaxillin−83.4−73.9−79.8−77.7−81.2
4,5α-Epoxy-6α-acetoxy-1(10)E,11(13)-germacradien-12,8α-olide−92.9−79.5no dock−80.9−89.6
4α,5β-Epoxy-8-epi-inunolide−77.1−67.0−80.3−70.2−77.2
Eremantholide C−91.3−70.7no dock−81.6−95.3
Eupatoriopicrin−100.1−91.3no dock−96.5−105.1
Goyazensolide−104.7−83.9no dock−84.3−98.8
Hanphyllin−79.3−64.9−64.6−75.7−76.4
8-(3'-Hydroxymethacryloxy)-hirsutinolide 13-acetate−120.2−90.6no dock−100.1−114.7
Ineupatorolide A−102.5−84.2no dock−89.1−95.0
Ivaxillin−82.2−70.1no dock−75.0−84.9
Molephantin−101.0−82.4no dock−82.3−101.2
Neurolenin B−95.7−76.0no dock−81.0−92.5
Neurolenin C−95.9−76.9no dock−82.0−93.3
Neurolenin D−99.7−76.0no dock−80.7−86.9
Parthenolide−82.1−63.5−84.6−75.2−76.9
Tagitinin C−97.0−79.4no dock−77.6−90.7
Tanachin−82.0−61.0−62.5−73.7−74.5
Tatridin A−87.0−65.2−97.2−70.9−77.8
8-Tigloylhirsutinolide 13-acetate−124.6−88.1no dock−91.5−109.1
Vernolide D−131.9−94.9no dock−100.0−110.4
Table 7. MolDock docking energies (kJ/mol) of guaianolide sesquiterpenoids with Leishmania major protein targets.
Table 7. MolDock docking energies (kJ/mol) of guaianolide sesquiterpenoids with Leishmania major protein targets.
Guaianolides LmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLmajNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
Arborescin−66.2−93.6−78.3−83.0−72.7−78.2−85.3−77.7−95.1−90.4−91.8−79.5
Carpesiolin−73.3−97.3−73.5−79.0−70.7−79.4−84.1−75.6−87.3−86.7−86.0−88.0
Confertin−62.4−90.0−72.4−73.5−75.8−72.7−81.5−70.1−74.8−94.4−78.3−83.7
Cynaropicrin−78.6−117.2−104.1−101.0−106.4−109.8−97.6−109.4−103.0−115.0−107.2−108.6
Damsin−64.9−102.1−74.1−77.0−77.4−83.2−79.4−78.2−74.8−89.1−77.5−85.1
11,13-Dehydrocompressanolide−72.6−94.1−77.6−78.6−74.9−76.8−78.7−80.1−85.0−93.3−81.7−92.6
Dehydrocostuslactone−63.2−86.9−76.2−73.1−72.7−69.5−75.1−73.5−82.1−86.5−83.8−79.8
Dehydroleucodine−66.9−89.5−85.2−84.2−80.6−79.9−83.7−84.2−94.2−90.9−93.3−83.2
Dehydrozaluzanin C−73.3−90.4−74.9−78.7−69.8−79.0−86.3−77.7−85.4−92.2−88.4−85.4
Diguaiaperfolin−127.8−154.5−130.6−116.8−135.7−129.4−114.3−129.7−124.3−129.9−144.6−151.8
4,15-Dinor-1,11(13)-xanthadiene-3,5β:12,8β-diolide−76.3−92.7−88.4−83.9−70.7−80.2−87.5−84.9−95.0−95.8−83.4−92.6
8-Epixanthatin-1β,5β-epoxide−78.0−108.0−77.8−89.0−84.5−88.3−87.1−88.3−92.0−106.8−89.5−95.4
Helenalin−67.2−92.8−74.6−74.6−80.7−77.5−80.1−79.0−84.0−86.4−87.5−87.2
Helenalin acetate−72.4−88.8−84.1−81.6−86.2−88.9−92.6−91.0−76.8−98.7−90.3−89.8
8β-Hydroxyzaluzanin D−81.2−102.8−95.6−87.0−89.7−91.1−98.7−90.2−88.3−94.1−93.9−98.9
Lactucin−68.8−100.7−84.2−91.9−93.4−87.9−89.7−91.7−104.1−92.2−103.6−89.3
Lactucopicrin−97.7−123.3−113.8−107.4−110.9−112.6−116.8−122.0−129.9−137.7−116.5−120.1
Mexicanin I−75.9−92.6−77.9−80.4−79.7−80.1−83.8−76.5−83.8−88.1−89.1−87.0
2-Oxo-8-tigloyloxyguaia-1(10),3-diene-6,12-olide-14-carboxylic acid−82.1−117.0−99.2−96.9−95.9−96.7−90.1−105.0−108.3−114.1−103.1−110.8
Peruvin−62.0−91.6−71.8−72.0−78.4−81.3−79.5−76.2−79.1−85.4−78.2−101.9
Psilostachyin−71.8−89.5−75.0−83.3−75.7−78.7−78.1−79.8−76.7−90.3−81.7−87.2
Psilostachyin C−72.4−91.5−74.3−75.8−79.5−72.8−82.2−78.3−79.9−92.5−82.3−89.7
Pungiolide A−91.6−96.7−96.8−116.1−106.0−109.6−111.8−122.8−108.3−122.6−107.3−117.5
Xanthipungolide−52.4−78.4−50.0−55.4−62.7−64.5−62.6−66.8−48.3−69.8−60.4−74.8
Zaluzanin D−68.6−103.0−93.1−86.7−80.0−93.1−90.8−93.7−89.1−96.5−97.1−95.3
Table 8. MolDock docking energies (kJ/mol) of guaianolide sesquiterpenoids with Leishmania donovani and L. mexicana protein targets.
Table 8. MolDock docking energies (kJ/mol) of guaianolide sesquiterpenoids with Leishmania donovani and L. mexicana protein targets.
Guaianolides LdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
Site 1Site 2Site 3
Arborescin−74.7−82.7−71.6−73.6−68.3−−91.9−65.5−82.7−88.1−75.1−86.5−73.8
Carpesiolin−76.7−78.5−61.5−69.7−66.5−91.8−61.9−83.4−85.7−88.6−94.1−82.1
Confertin−67.1−85.2−12.0−68.1−62.1-85.1−61.5−79.0−85.9−77.1−82.1−70.8
Cynaropicrin−80.5−99.7−57.3−92.8−88.0−121.8−97.2−114.7−127.0−91.8−94.1−90.1
Damsin−73.3−88.7−0.9−73.6−69.4−85.7−64.6−79.5−88.1−79.9-84.8−68.3
11,13-Dehydrocompressanolide−74.2−87.8−73.4−72.8−70.3−93.1−64.9−86.0−84.0−82.1−92.3−79.6
Dehydrocostuslactone−71.2−83.5-64.8−66.8−60.4−84.8−57.7−76.1−82.5−74.6−88.7−69.5
Dehydroleucodine−78.0−84.2−63.9−72.1−73.5−88.0−66.2−83.0−91.4−74.7−89.7−72.3
Dehydrozaluzanin C−74.4−86.1−79.0−76.0−68.3−91.0−70.8−82.9−85.4−80.5−99.5−77.9
Diguaiaperfolin−126.1−124.8−121.6−135.5−122.1−138.1−129.7−145.6−146.9−141.4−138.3−116.5
4,15-Dinor-1,11(13) -xanthadiene−3,5β:12,8β-diolide−80.7−89.5−78.7−75.7−69.9−84.6−67.7−82.2−86.4−81.3−90.6−76.7
8-Epixanthatin-1β,5β-epoxide−87.2−90.1−64.8−78.4−71.9−103.4−72.8−85.4−97.2−90.3−90.9−80.6
Helenalin−70.7−90.8−47.7−76.1−69.5−79.3−64.9−80.8−83.1−85.2−83.6−79.0
Helenalin acetate−74.2−77.2−76.9−74.9−78.5−105.5−74.7−87.6−99.3−86.9−78.5−79.9
8β-Hydroxyzaluzanin D−82.3−85.7−84.0−84.3−76.7−101.7−77.6−101.1−110.6−82.4−90.4−79.3
Lactucin−87.0−87.4−70.5−72.2−84.2−94.7−74.0−92.4−100.7−87.8−94.2−79.1
Lactucopicrin−114.3−111.2−65.0−114.4−99.5−126.7−108.5−119.9−120.4−115.0−116.1−107.3
Mexicanin I−76.3−80.5−74.7−71.3−70.4−88.9−63.0−81.9−86.6−88.8−92.3−76.5
2-Oxo-8-tigloyloxyguaia-1(10),3-diene-6,12-olide-14-carboxylic acid−97.4−97.0−91.1−101.5−81.8−117.3−82.4−111.8−118.9−96.8−115.4−86.6
Peruvin−66.7−83.6−64.1−74.6−62.7−83.0−61.5−83.0−88.5−79.1−83.6−74.1
Psilostachyin−69.6−85.7−6.0−73.5−65.8−91.5−63.4−85.3−92.7−78.1−88.8−70.5
Psilostachyin C−71.9−81.4−14.5−67.6−64.8−85.2−62.0−81.6−85.1−77.9−85.6-70.9
Pungiolide A−97.3−102.9−83.7−93.9−89.1−110.0−98.8−105.0−123.5−111.6−81.4−98.4
Xanthipungolide-50.4−63.3−3.8−55.4−57.3−75.0−43.1−67.5−66.9−57.2-83.7−54.3
Zaluzanin D−83.6−87.2−59.0−79.4−77.1−102.6−75.1−96.2−106.8−83.6−97.7−86.4
Table 9. MolDock docking energies (kJ/mol) of guaianolide sesquiterpenoids with Leishmania infantum protein targets.
Table 9. MolDock docking energies (kJ/mol) of guaianolide sesquiterpenoids with Leishmania infantum protein targets.
GuaianolidesLinfCYP51LinfGLO2LinfPnC1LinfTDR1LinfTR
Arborescin−79.3−64.1−59.5−70.7−95.1
Carpesiolin−81.0−64.2−65.0−72.2−82.4
Confertin−79.8−61.0−41.9−67.9−79.8
Cynaropicrin−106.2−85.8no dock−91.6−105.4
Damsin−78.9−68.5−70.3−68.3−79.2
11,13-Dehydrocompressanolide−77.9−66.7−68.8−74.1−78.2
Dehydrocostuslactone−73.5−61.4−68.8−69.1−82.4
Dehydroleucodine−79.6−65.7−72.1−71.5−92.8
Dehydrozaluzanin C−81.1−67.1−81.8−73.2−85.3
Diguaiaperfolin−141.0−118.8no dock−118.6−147.5
4,15-Dinor-1,11(13)-xanthadiene-3,5β:12,8β-diolide−79.7−67.8−70.8−76.8−84.4
8-Epixanthatin-1β,5β-epoxide−84.2−77.5−52.1−80.4−88.8
Helenalin−89.0−62.4−24.6−70.1−79.7
Helenalin acetate−85.9−71.7no dock−76.1−81.6
8β-Hydroxyzaluzanin D−97.3−75.2no dock−79.1−93.3
Lactucin−88.9−72.7no dock−85.0−99.8
Lactucopicrin−114.8−103.6no dock−106.7−101.6
Mexicanin I−79.1−64.4−83.3−73.2−79.3
2-Oxo-8-tigloyloxyguaia-1(10),3-diene-6,12-olide-14-carboxylic acid−100.1−94.1no dock−92.0−100.8
Peruvin−85.4−59.4no dock−68.9−75.4
Psilostachyin−85.7−69.7no dock−67.2−84.5
Psilostachyin C−74.1−59.9−55.5−67.0−82.1
Pungiolide A−109.4−97.5−69.9−105.6−114.8
Xanthipungolide−64.8−52.0−32.1−47.9−59.0
Zaluzanin D−92.4−75.7no dock−77.4−86.5
Table 10. MolDock docking energies (kJ/mol) of eudesmanolide sesquiterpenoids with Leishmania major protein targets.
Table 10. MolDock docking energies (kJ/mol) of eudesmanolide sesquiterpenoids with Leishmania major protein targets.
EudesmanolidesLmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLmajNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
Alantolactone−58.1−90.7−61.4−79.0−73.8−72.4−70.1−67.2−65.8−83.2−74.2−87.9
Anthecularin−56.1−77.7−62.7−68.7−67.2−65.7−73.7−72.3−59.6−70.9−72.6−85.9
Arbusculin B−54.8−79.8−67.6−64.4−66.2−71.8−75.8−64.1−66.6−75.9−73.3−79.8
α−Cyclocostunolide−63.7−85.3−75.1−72.6−69.7−70.6−74.7−69.1−78.5−86.1−77.1−77.2
β−Cyclocostunolide−64.6−85.9−67.0−73.5−67.9−69.7−76.1−66.7−81.9−83.2−73.0−77.9
Deacetyl−β−cyclopryethrosin−69.1−97.8−73.4−76.4−72.9−80.2−82.3−76.9−83.3−93.6−76.0−91.1
11,13−Dihydrovernodalin−78.0−110.6−91.9−100.3−89.7−99.7−99.0−106.2−103.4−114.7−104.0−94.5
Douglanin−66.7−90.4−76.9−71.6−71.9−69.6−77.8−74.7−79.4−88.2−77.1−78.5
Frullanolide−60.6−81.1−71.3−73.2−69.2−73.1−76.9−77.3−73.5−80.4−75.1−82.6
4−Hydroxyanthecotulide−76.1−104.1−90.1−103.0−88.3−101.7−95.0−100.5−100.8−103.2−98.1−112.3
8β−[4−Hydroxy−5−(5−hydroxytigloyloxy)-tigloyl]santamarin−109.5−128.9−116.3−125.3−117.8−115.9−113.3−117.5−130.2−153.1−128.3−127.1
Isoalantolactone−60.2−89.6−65.0−82.0−74.4−74.4−70.3−72.2−66.4−87.3−74.2−88.6
Ivalin−66.1−94.6−68.6−78.4−74.3−80.7−74.8−74.6−73.3−88.8−73.7−92.0
Ivalin acetate−77.4−93.6−87.4−87.4−83.2−89.5−90.8−89.6−91.6−104.5−87.8−83.4
Onoseriolide−72.4−92.4−82.8−81.4−78.5−79.8−88.5−83.8−88.6−101.4−81.3−82.5
2−Oxoalantolactone−59.1−94.0−64.8−79.6−76.3−78.0−75.0−69.7−68.4−85.5−75.0−91.1
Oxyonoseriolide−77.5−94.5−82.3−80.4−81.5−88.9−88.7−88.0−87.8−104.7−92.7−99.1
4−Peroxy−1,2,4,5−tetrahydro−α−santonin−63.3−97.6−72.6−71.0−72.5−74.1−87.3−80.3−90.1−85.2−76.6−82.4
Santamarin−65.3−86.0−74.9−72.7−72.6−71.6−80.5−73.1−79.0−89.3−79.4−79.4
α−Santonin−63.8−92.0−73.1−73.4−68.6−71.3−84.1−78.0−82.7−85.6−85.1−84.1
Sivasinolide−69.8−90.0−68.9−84.5−72.9−78.7−84.5−72.6−86.8−98.1−80.6−82.9
Trilobolide 6−isobutyrate−86.0−108.8−90.3−93.8−95.6−103.7−102.2−97.6−82.6−87.4−95.1−94.7
Trilobolide 6−methacrylate−78.4−103.8−87.9−85.0−94.2−111.3−87.6−97.6−78.9−87.5−92.1−92.2
Vernangulide B−91.2−118.3−108.7−105.8−105.6−113.0−99.8−107.1−122.9−125.3−105.0−111.9
Vernodalin−80.8−107.5−94.4−101.0−92.4−105.7−89.4−92.4−104.5−116.3−95.8−102.2
Vernodalol−82.5−112.8−100.1−99.1−96.4−97.3−94.5−99.4−100.0−107.8−94.6−90.2
Wedelolide A−88.3−109.9−95.0−83.5−94.0−109.6−84.2−103.7−83.1−131.6−96.2−98.4
Wedelolide B−88.0−113.0−91.2−87.0−94.2−107.4−99.0−107.4−82.8−134.0−102.8−94.9
Table 11. MolDock docking energies (kJ/mol) of eudesmanolide sesquiterpenoids with Leishmania donovani and L. mexicana protein targets.
Table 11. MolDock docking energies (kJ/mol) of eudesmanolide sesquiterpenoids with Leishmania donovani and L. mexicana protein targets.
EudesmanolidesLdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
Site 1Site 2Site 3
Alantolactone−67.1−78.3−55.0−64.4−62.6−79.8−57.8−74.6−78.6−72.2−79.7−77.9
Anthecularin−62.4−65.2−57.0−63.9−60.1−80.3−59.8−70.9−79.7−64.4−81.3−69.7
Arbusculin B−60.0−74.6−58.2−63.5−64.3−84.1−55.6−75.3−73.9−69.6−74.8−70.3
α−Cyclocostunolide−67.2−78.6−62.6−62.9−60.5−83.6−57.3−73.7−78.8−73.8−80.1−68.0
β−Cyclocostunolide−69.9−78.0−69.9−67.0−60.2−85.0−58.9−78.3−76.3−75.2−87.9−73.4
Deacetyl−β−cyclopryethrosin−73.4−82.9−63.3−72.8−71.5−92.2−63.3−84.0−84.6−78.1−88.1−81.4
11,13−Dihydrovernodalin−89.3−94.8−59.5−84.3−79.3−107.0−82.3−102.5−104.4−94.9−100.7−87.1
Douglanin−69.0−80.6−71.4−66.3−63.7−88.6−58.9−76.6−82.7−77.2−82.1−65.1
Frullanolide−61.5−77.8−65.2−63.1−67.0−79.4−58.7−75.6−82.1−72.5−86.1−72.8
4−Hydroxyanthecotulide−87.9−94.0−93.9−86.1−86.4−103.7−85.0−100.3−98.8−91.5−98.0−97.0
8β−[4−Hydroxy−5−(5−hydroxytigloyloxy)-tigloyl]santamarin−112.4−115.3−37.4−121.4−96.5−128.2−113.8−132.1−124.3−119.9−112.8−105.4
Isoalantolactone−69.9−83.1−70.6−64.4−59.3−82.4−56.8−77.4−80.0−69.7−85.1−74.0
Ivalin−77.3−84.5−74.6−73.2−62.5−84.1−62.0−80.9−83.6−73.4−88.9−70.0
Ivalin acetate−91.5−92.5−63.2−66.9−73.8−97.0−70.5−92.4−97.2−80.3−81.4−86.8
Onoseriolide−73.8−88.1−84.8−77.0−72.8−93.9−66.8−84.1−87.9−78.0−95.0−77.1
2−Oxoalantolactone−64.0−80.8−58.1−64.1−65.3−85.5−61.4−77.8−81.7−74.7−83.5−77.9
Oxyonoseriolide−77.9−84.5−61.8−78.5−78.5−95.4−70.4−84.6−98.4−80.6−103.9−79.3
4−Peroxy−1,2,4,5−tetrahydro−α−santonin−68.0−72.4−68.6−72.3−62.0−92.4−58.1−82.3−85.2−73.3−83.0−73.0
Santamarin−69.3−79.8−56.3−67.4−65.6−89.5−61.2−81.2−82.6−75.9−82.0−71.6
α−Santonin−68.9−78.3−71.0−68.6−65.5−85.6−57.8−82.5−80.7−69.1−85.4−72.0
Sivasinolide−71.6−85.1−61.8−73.5−68.1−94.9−62.3−84.7−88.4−77.9−91.5−76.4
Trilobolide 6−isobutyrate−82.4−83.4−71.3−80.7−79.8−99.2−84.5−103.2−96.5−89.4−92.1−72.4
Trilobolide 6−methacrylate−83.4−80.8−20.7−82.7−70.3−99.2−88.3−107.3−94.9−92.7−87.2−74.7
Vernangulide B−93.8−106.6−126.8−96.1−90.5−121.5−100.6−120.1−116.6−105.6−107.5−104.7
Vernodalin−84.6−94.2−79.2−87.4−80.6−110.8−81.5−106.2−104.5−106.1−99.5−94.0
Vernodalol−88.4−96.3−50.6−83.9−84.1−105.2−93.5−99.8−103.5−99.1−103.4−83.2
Wedelolide A−87.9−68.5−85.5−91.6−84.0−96.0−90.3−114.9−103.2−107.4−92.9−92.7
Wedelolide B−81.5−64.3−88.3−97.5−79.2−96.0−92.2−127.4−102.4−108.8−102.6−96.0
Table 12. MolDock docking energies (kJ/mol) of eudesmanolide sesquiterpenoids with Leishmania infantum protein targets.
Table 12. MolDock docking energies (kJ/mol) of eudesmanolide sesquiterpenoids with Leishmania infantum protein targets.
EudesmanolidesLinfCYP51LinfGLO2LinfPnC1LinfTDR1LinfTR
Alantolactone−71.3−60.0no dock−66.1−75.5
Anthecularin−70.8−47.5−58.4−62.3−71.0
Arbusculin B−71.0−58.8−12.7−62.1−73.6
α−Cyclocostunolide−70.4−60.3−82.7−69.1−79.0
β−Cyclocostunolide−75.9−62.0−79.0−71.6−73.1
γ−Cyclocostunolide−71.0−57.5−12.1−62.2−67.4
Deacetyl−β−cyclopryethrosin−74.8−64.8−75.5−71.5−82.2
11,13−Dihydrovernodalin−105.4−83.0no dock−85.8−95.4
Douglanin−76.4−60.7−10.6−67.9−80.1
Frullanolide−75.2−61.3−55.4−70.5−74.5
4−Hydroxyanthecotulide−90.2−82.6−68.4−85.4−92.1
8β−[4−Hydroxy−5−(5−hydroxytigloyloxy)-tigloyl]santamarin−117.8−98.9no dock−103.4−114.9
Isoalantolactone−69.1−57.8−31.1−64.3−74.2
Ivalin−72.9−65.0−16.1−65.6−80.5
Ivalin acetate−88.7−72.0no dock−76.6−91.2
Onoseriolide−82.0−70.0−24.6−71.8−82.4
2−Oxoalantolactone−73.4−57.6no dock−68.1−79.4
Oxyonoseriolide−86.7−71.3−11.8−78.4−87.9
4−Peroxy−1,2,4,5−tetrahydro−α−santonin−80.6−73.2−66.0−66.5−78.2
Santamarin−67.8−59.5−85.2−71.3−81.3
α−Santonin−74.2−69.4−44.0−65.5−86.4
Sivasinolide−75.2−63.3−72.1−72.5−81.1
Trilobide 6−isobutyrate−97.9−82.0no dock−80.3−90.2
Trilobide 6−methacrylate−96.0−86.3no dock−77.2−90.2
Vernangulide B−105.2−98.6no dock−99.3−99.0
Vernodalin−105.9−88.9no dock−86.6−96.9
Vernodalol−103.1−79.4no dock−88.9−96.8
Wedelolide A−97.6−80.8no dock−90.4−99.4
Wedelolide B−105.8−77.6no dock−92.8−96.6
Table 13. MolDock docking energies (kJ/mol) of miscellaneous sesquiterpenoids with Leishmania major protein targets.
Table 13. MolDock docking energies (kJ/mol) of miscellaneous sesquiterpenoids with Leishmania major protein targets.
Miscellaneous SesquiterpenoidsLmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLmajNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
Alloaromadendrene−56.8−81.7−67.0−68.2−66.1−71.1−74.3−68.2−91.9−70.7−70.0−76.6
Aromadendrene−56.9−78.5−68.4−66.9−64.7−70.2−73.2−67.9−99.4−73.2−72.4−72.2
1,10−Bisaboladiene−3,4−diol−67.4−92.7−81.0−82.8−79.8−87.5−89.2−82.9−102.6−91.1−80.7−89.5
α−Bisabolol−75.2−92.5−76.3−77.5−75.6−89.9−74.7−79.9−110.6−93.8−80.3−83.2
Corymbolone−56.5−82.2−59.1−67.5−70.2−66.5−69.5−65.5−59.5−77.2−68.3−85.9
α−Eudesmol−60.9−80.3−64.8−70.7−68.1−66.0−66.0−74.2−86.8−83.1−76.9−74.7
β−Eudesmol−58.8−83.4−69.6−69.6−66.5−68.2−72.7−67.3−89.6−76.9−68.1−79.1
1(10),5−Germacradien−4−ol−62.0−88.1−68.8−69.1−73.3−70.1−76.0−72.2−100.0−87.1−75.0−88.6
Germacrene D−57.9−81.4−66.6−65.1−70.8−68.8−69.7−69.9−96.7−77.7−70.6−81.8
Gossypol−59.1−106.1−85.2−89.5−83.9−104.6−98.4−111.5−120.6−92.7−108.0−90.7
Gossypol−6,6'−dimethylether−90.8−108.3−84.1−95.0−85.6−95.5−84.6−114.3−117.5−88.0−108.6−100.3
Gossypol−6−methylether−93.1−109.1−85.9−93.7−103.2−116.8−102.1−113.3−122.2−94.1−111.6−95.6
Homalomenol C−67.8−88.7−65.1−69.4−72.6−72.4−76.6−74.7−92.6−83.9−75.5−88.6
1−Hydroperoxy−10(14),11−guaiadiene−60.7−85.4−70.4−70.7−69.0−74.0−77.5−78.5−96.5−83.6−76.5−83.7
10−Hydroperoxy−1,11−guaiadiene−64.6−82.2−76.5−73.3−74.6−77.5−77.5−82.7−109.1−86.4−80.1−79.9
14−Hydroperoxy−1(10),11−guaiadiene−71.5−88.0−88.1−79.2−78.4−78.5−80.0−82.3−111.6−87.9−79.1−86.6
Kudtriol−60.6−86.7−65.3−68.9−72.5−71.5−66.2−69.2−81.5−82.3−68.0−80.5
5−epi−Kudtriol−59.9−86.5−69.2−68.4−70.4−78.2−75.8−75.8−65.9−77.9−65.1−83.0
Longifolene−52.1−75.8−50.0−62.3−59.6−58.9−63.0−66.7−61.3−62.3−63.1−70.8
Mukaadial−67.0−89.5−71.1−72.7−67.3−75.0−76.6−72.0−80.7−79.2−82.3−81.8
Mustakone−47.5−78.0−61.9−62.0−64.5−64.2−67.6−67.5−66.1−71.7−65.4−81.7
Muzigadial−64.6−93.9−66.8−70.6−65.0−70.6−74.1−66.3−81.5−81.9−68.5−76.8
Nerolidol−69.5−91.4−86.4−86.5−81.2−93.0−84.3−89.8−117.0−100.5−87.9−94.2
Oplopanone−59.4−81.9−69.4−66.1−68.2−70.8−73.0−71.7−106.4−76.9−74.0−74.2
10,12−Peroxycalamenene−41.0−71.0−57.9−57.4−60.8−65.9−66.3−74.3−70.6−69.3−68.4−70.7
Plagiochilin A−83.4−103.9−94.1−94.1−93.6−88.5−95.7−92.7−132.3−102.9−106.0−105.9
Polygodial−61.3−86.0−70.7−71.6−64.8−71.0−76.9−66.6−91.1−86.3−71.5−80.4
Zingiberene−3,6−α−peroxide−62.3−89.4−75.8−75.4−76.0−82.6−68.3−84.9−87.4−92.0−76.8−88.2
Zingiberene−3,6−β−peroxide−62.2−86.9−73.6−75.4−74.9−78.7−72.4−84.7−89.9−82.0−73.7−84.9
Table 14. MolDock docking energies (kJ/mol) of miscellaneous sesquiterpenoids with Leishmania donovani and L. mexicana protein targets.
Table 14. MolDock docking energies (kJ/mol) of miscellaneous sesquiterpenoids with Leishmania donovani and L. mexicana protein targets.
Miscellaneous SesquiterpenoidsLdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
Site 1Site 2Site 3
Alloaromadendrene−66.6−77.8−46.3−58.8−61.3−78.3−57.1−71.4−79.0−62.3−79.7−68.9
Aromadendrene−66.1−72.0−56.6−62.4−57.1−75.0−54.4−71.9−79.4−65.5−77.1−65.1
1,10−Bisaboladiene−3,4−diol−73.0−82.3−74.6−85.5−70.9−94.2−71.9−78.6−88.2−76.9−84.5−80.0
α−Bisabolol−75.2−76.8−68.1−81.0−65.2−85.2−67.0−84.8−90.3−75.7−79.7−77.7
Corymbolone−60.9−72.2−62.0−63.5−60.6−74.4−56.1−70.5−74.6−72.4−80.2−69.4
6α,9α−Dihydroxypolygodial−65.8−86.7−61.9−72.3−65.5−88.4−58.7−77.1−83.6−74.4−91.4−69.6
α−Eudesmol−62.3−74.4−49.2−57.4−57.2−78.4−53.9−76.3−73.5−64.3−82.9−67.2
β−Eudesmol−66.1−74.1−57.0−63.4−58.8−75.1−56.5−77.8−72.4−65.5−83.0−68.3
1(10),5−Germacradien−4−ol−69.7−78.5−49.2−70.5−62.2−81.5−58.6−75.2−78.1−68.4−84.1−74.8
Germacrene D−65.0−74.6−64.4−68.3−60.1−77.0−58.3−70.1−73.5−64.9−82.0−71.3
Gossypol−79.2−86.4−88.4−64.5−81.7−117.4−76.4−116.4−110.5−96.9−93.4−86.4
Gossypol−6,6'−dimethylether−89.6−82.6−90.2−82.3−71.9−112.2−81.8−119.8−113.9−103.5−96.5−84.3
Gossypol−6−methylether−82.2−90.0−87.5−82.4−69.4−113.0−75.3−115.2−111.7−103.6−101.0−83.4
Homalomenol C−66.5−75.6−26.8−65.5−64.4−89.4−63.4−74.5−87.0−68.4−84.5−73.1
1−Hydroperoxy−10(14),11−guaiadiene−59.3−78.1−59.8−61.2−63.7−85.3−61.7−73.4−81.5−74.5−79.2−68.5
10−Hydroperoxy−1,11−guaiadiene−77.0−82.0−67.9−66.3−66.3−83.7−60.1−80.2−86.0−73.5−85.7−78.9
14−Hydroperoxy−1(10),11−guaiadiene−78.4−92.8−85.2−69.2−70.4−93.9−67.8−79.5−87.7−75.2−91.0−79.6
Kudtriol−69.5−78.5−66.2−65.6−61.3−79.2−58.9−73.8−78.6−69.7−93.0−70.4
5−epi−Kudtriol−59.0−78.2−65.4−66.2−69.3−79.6−55.7−76.8−77.6−70.7−83.7−68.5
Longifolene−52.4−69.7−35.7−56.3−57.6−74.0−52.4−63.5−68.1−63.1−66.8−60.8
Mukaadial−65.9−86.9−61.9−72.3−72.0−92.6−58.7−77.1−83.7−74.5−91.5−69.6
Mustakone−57.7−57.0−61.7−59.3−56.1−76.2−53.7−69.0−72.7−63.2−73.7−63.2
Muzigadial−70.3−85.5−15.2−62.1−66.3−78.6−57.9−76.5−80.4−73.1−81.2−71.5
Nerolidol−79.6−82.0−87.3−76.3−74.5−91.1−79.5−84.3−87.3−76.5−91.7−85.8
Oplopanone−68.5−78.9−64.1−65.2−59.8−78.2−58.4−71.5−77.0−67.2−78.5−68.5
10,12−Peroxycalamenene−51.6−70.8−62.9−54.6−58.3−71.8−49.9−71.3−66.5−61.4−69.9−62.4
Plagiochilin A−96.2−89.1−95.1−81.9−78.8−105.9−75.5−99.4−99.8−97.9−87.5−89.2
Polygodial−60.0−80.5−57.6−68.6−62.1−81.9−55.2−73.3−78.4−69.2−84.7−76.3
Zingiberene−3,6−α−peroxide−75.1−71.7−80.1−74.3−67.0−83.7−67.1−80.7−79.9−74.0−81.1−76.1
Zingiberene−3,6−β−peroxide−71.6−75.1−77.1−76.2−60.7−84.3−66.0−74.9−83.0−67.0−87.3−74.6
Table 15. MolDock docking energies (kJ/mol) of miscellaneous sesquiterpenoids with Leishmania infantum protein targets.
Table 15. MolDock docking energies (kJ/mol) of miscellaneous sesquiterpenoids with Leishmania infantum protein targets.
Miscellaneous SesquiterpenoidsLinfCYP51LinfGLO2LinfPnC1LinfTDR1LinfTR
Alloaromadendrene−66.8−57.0−52.9−61.7−67.2
Aromadendrene−60.8−59.7−60.8−61.6−76.8
1,10−Bisaboladiene−3,4−diol−75.6−70.8−63.5−72.1−85.0
α−Bisabolol−76.5−74.1−73.4−75.0−74.7
Corymbolone−65.9−54.6−49.1−59.4−65.3
6α,9α−Dihydroxypolygodial−75.7−62.3−23.0−63.6−78.0
α−Eudesmol−62.6−58.1−28.2−59.1−69.5
β−Eudesmol−68.0−59.6−23.9−64.3−69.7
1(10),5−Germacradien−4−ol−70.4−58.4−52.6−63.6−70.2
Germacrene D−64.6−57.4−62.7−68.0−70.2
Gossypol−109.9−99.6no dock−86.6−97.0
Gossypol−6,6'−dimethylether−109.5−95.1no dock−88.7−101.1
Gossypol−6−methylether−113.1−99.6no dock−94.5−100.9
Homalomenol C−72.3−57.3−41.9−64.4−68.5
1−Hydroperoxy−10(14),11−guaiadiene−74.5−56.7−15.4−62.9−72.8
10−Hydroperoxy−1,11−guaiadiene−79.3−66.5−38.7−67.3−75.4
14−Hydroperoxy−1(10),11−guaiadiene−81.4−67.2−69.9−74.2−74.4
Kudtriol−68.1−51.5no dock−65.3−72.4
5−epi−Kudtriol−67.9−61.6no dock−63.0−71.5
Longifolene−64.9−49.4−48.0−54.6−61.5
Mukaadial−74.9−61.5−21.0−63.7−78.0
Mustakone−63.5−57.5−18.1−55.3−63.3
Muzigadial−72.6−56.5−66.6−65.1−84.6
Nerolidol−79.3−72.3−72.0−79.1−82.5
Oplopanone−65.7−59.4−55.6−63.2−69.2
10,12−Peroxycalamenene−65.2−46.6no dock−58.2−70.5
Plagiochilin A−95.9−79.6no dock−80.5−89.3
Polygodial−72.1−57.6−45.3−62.8−72.3
Zingiberene−3,6−α−peroxide−77.7−65.4−65.8−66.7−75.1
Zingiberene−3,6−β−peroxide−69.8−65.5−51.2−62.7−72.9
The guaianolide with the strongest docking energy was diguaiaperfolin, probably owing to its dimeric structure and larger molecular weight (716.77 amu). This ligand did show notable docking (−154.5 kJ/mol) with LmajDHODH as well as with LmajUGPase (docking energy = −151.8 kJ/mol). 8β-[4-Hydroxy-5-(5-hydroxytigloyloxy)tigloyl]santamarin was the strongest-docking eudesmanolide, and this ligand showed docking selectivity to LmajMetRS (docking energy = −153.1 kJ/mol). The proteins most strongly targeted by both the guaianolides and the eudesmaolides were also LmajMetRS and LmajDHODH. Interestingly, the miscellaneous sesquiterpenoids preferentially targeted L. major pteridine reductase 1 (LmajPTR1), and plagiochilin A showed notable selectivity (docking energy = −132.2 kJ/mol) for this protein.
Several electrophilic sesquiterpenoids have exhibited antiprotozoal activity [5] and many of these showed docking selectivity to LmajDHODH. The active site of this protein has some potential nucleophilic residues, namely Ser 69, Ser 196, and Cys 131. Suitably oriented electrophilic ligands could form covalent bonds with these nucleophiles and thus inhibit the enzyme. Thus, for example, the germacranolide tatridin A docked preferentially to LmajDHODH, and the lowest-energy docked pose oriented the electrophilic carbon of the α-methylene lactone moiety close to the sulfur atom of Cys 131 (see Figure 6). Similarly, the lowest-energy docked orientation of 11-epi-ivaxillin places one of the epoxide groups near to the sulfur atom of Cys 131 (Figure 7). Conversely, the lowest-energy docked pose of neurolenin B is such that the electrophilic carbon of the α-methylene lactone group of the ligand is near the hydroxyl group of Ser 69 (Figure 8). The ligand with the lowest docking energy to LmajDHODH was the guaianolide dimer diguaiaperfolin (−154.5 kJ/mol). The lowest-energy pose for this ligand placed the cyclopentenone moiety near the sulfur atom of Cys 131 (Figure 9).
Figure 6. Lowest-energy docked pose of tatridin A with L. major dihydroorotate dehydrogenase (LmajDHODH, PDB 3mhu). The cofactor, riboflavin monophosphate, is shown as a space-filling structure.
Figure 6. Lowest-energy docked pose of tatridin A with L. major dihydroorotate dehydrogenase (LmajDHODH, PDB 3mhu). The cofactor, riboflavin monophosphate, is shown as a space-filling structure.
Molecules 18 07761 g006
Figure 7. Lowest-energy docked pose of 11-epi-ivaxillin with L. major dihydroorotate dehydrogenase (LmajDHODH, PDB 3mhu). The cofactor, riboflavin monophosphate, is shown as a space-filling structure.
Figure 7. Lowest-energy docked pose of 11-epi-ivaxillin with L. major dihydroorotate dehydrogenase (LmajDHODH, PDB 3mhu). The cofactor, riboflavin monophosphate, is shown as a space-filling structure.
Molecules 18 07761 g007
Figure 8. Lowest-energy docked pose of neurolenin B with L. major dihydroorotate dehydrogenase (LmajDHODH, PDB 3mhu). The cofactor, riboflavin monophosphate, is shown as a space-filling structure.
Figure 8. Lowest-energy docked pose of neurolenin B with L. major dihydroorotate dehydrogenase (LmajDHODH, PDB 3mhu). The cofactor, riboflavin monophosphate, is shown as a space-filling structure.
Molecules 18 07761 g008
Figure 9. Lowest-energy docked pose of diguaiaperfolin with L. major dihydroorotate dehydrogenase (LmajDHODH, PDB 3mhu). The cofactor, riboflavin monophosphate, is shown as a space-filling structure.
Figure 9. Lowest-energy docked pose of diguaiaperfolin with L. major dihydroorotate dehydrogenase (LmajDHODH, PDB 3mhu). The cofactor, riboflavin monophosphate, is shown as a space-filling structure.
Molecules 18 07761 g009

2.3. Diterpenoid Docking

Structures of diterpenoids are shown in Figure 10, Figure 11, Figure 12, Figure 13, Figure 14, Figure 15, Figure 16, Figure 17 and Figure 18. Docking energies of the diterpenoids are assembled in Table 16, Table 17, Table 18, Table 19, Table 20, Table 21, Table 22, Table 23, Table 24, Table 25, Table 26, Table 27 and Table 28. The diterpenoids ligands generally favored docking to L. mexicana glycerol-3-phosphate dehydrogenase (LmexGPDH). In particular, the kaurane diterpenoids strongly docked to this target. In addition to LmexGPDH, labdane diterpenoids showed docking preferences for LmajMetRS and LmajDHODH. The strongest-docking ligands were the cinnamoyl cassanes 6β-O-cinnamoyl-12-hydroxy-(13)15-en-16,12-olide-18-cassaneoic acid and 6β-O-2',3'-dihydro-cinnamoyl-12-hydroxy-(13)15-en-16,12-olide-18-cassaneoic acid. These two ligands showed significant docking preference to LmajMetRS and LmexPMM.
Figure 10. Abietane diterpenoids examined in this study.
Figure 10. Abietane diterpenoids examined in this study.
Molecules 18 07761 g010
Figure 11. Clerodane diterpenoids examined in this study.
Figure 11. Clerodane diterpenoids examined in this study.
Molecules 18 07761 g011
Figure 12. Labdane diterpenoids examined in this study.
Figure 12. Labdane diterpenoids examined in this study.
Molecules 18 07761 g012
Figure 13. Kaurane diterpenoids examined in this study.
Figure 13. Kaurane diterpenoids examined in this study.
Molecules 18 07761 g013
Figure 14. Pimarane diterpenoids examined in this study.
Figure 14. Pimarane diterpenoids examined in this study.
Molecules 18 07761 g014
Figure 15. Cassane diterpenoids examined in this study.
Figure 15. Cassane diterpenoids examined in this study.
Molecules 18 07761 g015
Figure 16. Icetaxane diterpenoids examined in this study.
Figure 16. Icetaxane diterpenoids examined in this study.
Molecules 18 07761 g016
Figure 17. Mulinane diterpenoids examined in this study.
Figure 17. Mulinane diterpenoids examined in this study.
Molecules 18 07761 g017
Figure 18. Miscellaneoous diterpenoids examined in this study.
Figure 18. Miscellaneoous diterpenoids examined in this study.
Molecules 18 07761 g018
Table 16. MolDock docking energies (kJ/mol) of abietane diterpenoids with Leishmania major protein targets.
Table 16. MolDock docking energies (kJ/mol) of abietane diterpenoids with Leishmania major protein targets.
Abietane diterpenoidsLmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLdonNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
Abieta−7,13−diene−71.5−80.8−79.3−80.3−76.3−69.7−82.2−77.0−74.7−96.9−78.1−78.3
ar−Abietatriene−12,16−diol−14,16−oxide−74.0−97.8−78.9−96.2−78.0−74.8−98.2−83.2−73.8−89.0−84.6−77.8
ar−Abietatrien−12−ol−6,7−dione−14,16−oxide−66.1−91.8−86.1−79.4−72.8−74.2−98.2−83.6−84.5−92.7−91.4−83.4
epi−Abietic acid−75.3−93.5−81.8−74.9−84.0−78.1−86.1−80.7−82.1−99.8−87.3−84.7
4− epi−Abietol−71.9−87.6−81.8−80.4−80.9−69.3−83.4−74.8−78.1−96.3−81.0−82.3
Cryptotanshinone−69.2−93.7−74.6−81.3−59.6−78.3−91.6−83.4−81.2−105.2−86.5−78.6
12− O−Deacetyl−6−O−acetyl−18−acetyloxycoleon Q−81.2−89.0−95.0−89.7−99.9−79.5−95.5−111.8−93.9−94.2−88.9−114.2
12− O−Deacetyl−6−O−acetyl−19−acetyloxycoleon Q−76.3−104.3−82.9−93.8−101.2−75.4−100.7−107.4−84.3−99.0−92.0−96.9
12−Deoxyroyleanone−78.2−79.2−74.3−74.8−72.9−73.1−76.5−83.6−86.4−85.9−77.6−77.4
9α,13α− epi−Dioxyabiet−8(14)−en−18−oic acid−65.5−88.2−79.9−82.1−80.1−64.0−89.6−79.4−71.2−89.5−88.2−81.6
9α,13α− epi−Dioxyabiet−8(14)en−18−ol−47.3−86.6−76.2−78.7−72.3−65.3−74.4−76.8−72.7−81.5−74.0−71.2
Dracocephalone A−66.5−82.6−70.8−76.6−71.9−66.7−93.0−83.2−87.4−83.4−72.9−78.7
Dracocequinone A−66.6−84.4−74.5−76.0−74.1−75.4−94.8−83.5−73.8−87.6−76.4−82.6
Dracocequinone B−74.5−89.1−71.5−78.4−78.4−76.6−83.4−81.9−76.0−88.7−77.3−88.2
Ferruginol−68.7−90.3−81.0−81.7−76.0−71.3−85.3−82.2−83.7−99.3−83.4−81.2
Hinokiol−77.9−88.2−85.2−75.8−79.1−62.3−84.5−74.9−77.9−92.4−77.7−74.0
Hinokiol−1−one−79.9−87.2−87.6−80.6−81.8−70.4−86.5−76.7−81.6−97.4−82.2−77.5
7β−Hydroxyabieta−8,13−diene−11,12−dione−76.2−77.8−94.0−83.9−79.9−76.5−91.4−84.1−81.3−95.2−86.2−83.9
7α−Hydroxyabieta−8,11,13−triene−76.8−85.3−84.5−75.4−69.1−66.7−83.0−81.3−77.8−90.9−78.7−82.0
14−Hydroxy−7,9(11),13−abietatriene−6,12−dione−74.8−83.5−71.0−82.1−68.6−76.5−88.3−76.2−78.6−94.8−84.7−85.5
11−Hydroxy−7,9(11),13−abietatrien−12−one−72.5−82.5−80.1−82.3−75.3−72.1−83.7−73.6−82.4−95.9−74.1−80.4
12−Hydroxy−8,12−abietadiene−3,11,14−trione−75.9−86.0−75.2−79.9−83.7−73.9−90.3−84.7−94.2−85.3−79.6−86.0
1β−Hydroxycryptotanshinone−74.7−96.0−70.0−80.8−70.1−79.2−99.1−83.8−84.0−104.4−90.0−78.5
7−Hydroxy−12−methoxy−20− nor−abieta−1,5(10),7,9,12−pentaen−6,14−dione−66.6−91.6−75.4−80.9−72.5−79.2−92.5−82.4−83.6−94.2−83.7−81.5
14−Hydroxy−6−oxoferruginol−56.1−91.1−72.3−85.5−75.7−73.9−87.0−79.5−83.6−90.3−75.2−79.3
6−Hydroxysalvinolone−77.1−83.3−76.6−76.2−77.6−72.4−82.3−81.2−82.7−93.7−87.1−86.5
Komarovinone A−82.0−82.4−79.2−73.1−72.7−67.1−96.1−83.5−84.6−100.0−77.6−84.0
1−Oxocryptotanshinone−75.8−102.9−74.7−77.9−70.6−75.4−96.6−79.8−82.4−114.6−89.3−78.0
1−Oxomiltirone−71.6−84.7−78.4−77.8−71.6−76.8−90.3−82.8−79.8−104.9−82.4−79.1
Royleanone−73.5−84.0−72.2−81.9−79.6−72.3−90.5−82.7−91.0−87.9−80.5−83.9
Sugiol−67.6−90.5−82.4−73.2−81.5−53.1−76.2−84.0−77.2−97.3−84.0−84.4
Taxodione−79.0−87.2−77.8−83.5−75.7−72.3−85.6−78.3−69.0−90.7−82.0−80.4
6,11,12,16−Tetrahydroxy−5,8,11,13−abietatetraen−7−one−78.2−88.6−81.5−82.9−80.2−73.3−95.1−87.8−88.3−93.8−83.4−90.7
6,12,14−Trihydroxyabieta−5,8,11,13−tetraen−7−one−69.6−86.1−70.6−78.7−73.9−80.8−89.4−84.6−81.5−97.4−85.9−83.5
4− epi−Triptobenzene L−68.9−94.9−89.9−81.7−79.6−76.6−87.6−85.9−83.3−88.2−82.4−82.4
Uncinatone−84.3−81.8−81.6−85.9−62.1−74.5−86.5−86.5−108.8−107.7−95.6−77.6
Table 17. MolDock docking energies (kJ/mol) of abietane diterpenoids with Leishmania donovani and L. mexicana protein targets.
Table 17. MolDock docking energies (kJ/mol) of abietane diterpenoids with Leishmania donovani and L. mexicana protein targets.
Abietane diterpenoidsLdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
Site 1Site 2Site 3
Abieta−7,13−diene−73.0−84.2−70.8−69.7−69.1−92.6−62.7−76.6−81.3−71.3−74.2−62.9
ar−Abietatriene−12,16−diol−14,16−oxide−77.9−84.2−70.5−74.8−73.7−104.7−74.6−82.6−104.4−83.5−84.9−73.1
ar−Abietatrien−12−ol−6,7−dione−14,16−oxide−76.3−90.1−75.9−74.2−69.1−102.3−68.9−93.5−99.2−87.3−90.1−72.1
epi−Abietic acid−77.4−86.4−67.6−78.1−60.9−97.6−67.8−81.5−84.0−74.5−91.0−68.6
4− epi−Abietol−77.2−88.0−69.7−69.3−68.1−94.0−66.3−78.8−78.0−75.2−72.6−65.9
Cryptotanshinone−77.5−80.5−84.5−78.3−66.6−101.9−71.1−84.4−95.4−75.3−71.7−65.3
12− O−Deacetyl−6−O−acetyl−18−acetyloxycoleon Q−78.6−93.4−41.3−79.5−86.6−108.4−87.4−109.1−102.6−110.1−102.8−86.7
12− O−Deacetyl−6−O−acetyl−19−acetyloxycoleon Q−99.6−80.4−45.8−75.4−90.6−105.1−87.4−109.7−101.1−96.2−88.7−73.6
12−Deoxyroyleanone−80.4−86.7−72.1−73.1−68.2−99.6−62.7−82.7−84.0−73.0−87.4−68.4
9α,13α− epi−Dioxyabiet−8(14)−en−18−oic acid−59.0−88.1−51.5−64.0−71.2−100.3−69.3−86.9−82.4−77.1−85.3−76.1
9α,13α− epi−Dioxyabiet−8(14)en−18−ol−55.8−76.8−58.2−65.3−63.2−96.6−66.9−81.2−79.7−71.6−74.1−70.9
Dracocephalone A−74.3−81.2−73.4−66.7−69.5−103.5−64.4−82.2−84.9−74.8−81.2−68.1
Dracocequinone A−71.2−83.6−77.7−75.4−66.1−104.7−66.2−82.5−84.7−72.0−79.9−68.9
Dracocequinone B−75.7−81.6−72.0−76.6−67.4−107.2−67.7−83.7−82.8−72.2−77.3−76.7
Ferruginol−70.5−91.1−75.4−71.3−71.2−96.7−75.1−83.7−82.9−75.3−76.1−69.8
Hinokiol−77.1−87.8−72.0−62.3−71.1−95.9−65.9−79.3−81.4−71.9−73.5−63.7
Hinokiol−1−one−77.0−86.1−72.7−70.4−70.9−99.6−63.7−80.2−79.7−69.7−77.2−67.6
7β−Hydroxyabieta−8,13−diene−11,12−dione−83.8−79.8−80.7−76.5−69.0−100.8−69.4−89.6−91.6−77.9−83.9−76.8
7α−Hydroxyabieta−8,11,13−triene−75.4−76.3−73.1−66.7−68.1−96.5−70.5−78.2−82.5−74.8−82.9−67.0
14−Hydroxy−7,9(11),13−abietatriene−6,12−dione−74.5−89.5−81.6−76.5−72.7−96.0−68.6−86.8−85.3−76.6−75.3−67.9
11−Hydroxy−7,9(11),13−abietatrien−12−one−79.6−87.1−76.1−72.1−61.8−97.7−68.7−83.9−78.1−76.3−78.1−69.9
12−Hydroxy−8,12−abietadiene−3,11,14−trione−79.7−82.0−75.6−73.9−66.2−109.4−68.9−92.5−88.8−75.3−84.8−71.0
1b−Hydroxycryptotanshinone−78.4−84.0−80.5−79.2−68.3−98.5−71.1−87.5−94.5−77.8−74.5−70.8
7−hydroxy−12−methoxy−20− nor−abieta−1,5(10),7,9,12−pentaen−6,14−dione−75.6−87.7−69.1−79.2−67.5−102.0−68.2−87.1−88.6−68.1−79.9−65.2
14−Hydroxy−6−oxoferruginol−66.5−93.7−78.2−73.9−71.7−96.9−61.8−87.2−88.7−80.8−70.6−68.5
6−Hydroxysalvinolone−78.8−78.9−77.6−72.4−62.2−94.7−66.0−89.9−94.9−84.3−75.8−69.0
Komarovinone A−80.3−81.2−81.2−67.1−65.0−98.3−69.2−90.1−86.5−80.4−70.8−73.4
1−Oxocryptotanshinone−76.1−80.4−71.9−75.4−66.9−95.0−69.1−85.7−89.6−79.8−77.1−65.4
1−Oxomiltirone−74.3−71.4−78.1−76.8−61.6−92.9−65.3−81.5−84.5−76.6−71.2−66.5
Royleanone−80.1−85.8−75.6−72.3−61.3−102.2−65.3−87.9−90.8−77.4−73.0−69.1
Sugiol−73.9−78.4−77.3−53.1−65.1−95.8−66.2−85.3−86.3−79.1−71.1−71.8
Taxodione−80.6−94.1−77.9−72.3−68.0−97.3−70.5−89.2−81.6−79.0−75.8−49.5
6,11,12,16−Tetrahydroxy−5,8,11,13−abietatetra−en−7−one−79.0−86.0−84.9−73.3−66.9−96.1−65.9−95.6−105.1−87.5−77.6−75.5
6,12,14−Trihydroxyabieta−5,8,11,13−tetraen−7−one−72.7−84.9−81.2−80.8−72.6−97.7−62.5−89.1−89.8−89.2−77.1−62.8
4− epi−Triptobenzene L−76.3−89.7−76.3−76.6−72.3−101.5−70.0−85.1−85.7−77.6−77.9−72.5
Uncinatone−85.4−73.3−72.1−74.5−69.8−89.0−65.3−84.4−94.8−84.1−89.2−64.4
Table 18. MolDock docking energies (kJ/mol) of abietane diterpenoids with Leishmania infantum protein targets.
Table 18. MolDock docking energies (kJ/mol) of abietane diterpenoids with Leishmania infantum protein targets.
Abietane diterpenoidsLinfCYP51LinfGLO2LinfPnC1LinfTDR1LinfTR
Abieta−7,13−diene−76.4−71.1no dock−65.7−72.6
ar−Abietatriene−12,16−diol−14,16−oxide−87.3−76.4no dock−74.3−78.4
ar−Abietatrien−12−ol−6,7−dione−14,16−oxide−84.7−72.7no dock−76.8−83.5
epi−Abietic acid−83.8−67.7no dock−66.4−74.5
4− epi−Abietol−78.5−68.9no dock−64.6−72.4
Cryptotanshinone−83.6−67.0no dock−71.5−84.1
12− O−Deacetyl−6−O−acetyl−18−acetyloxycoleon Q−106.3−80.7no dock−88.6−103.4
12− O−Deacetyl−6−O−acetyl−19−acetyloxycoleon Q−105.1−85.8no dock−87.3−98.2
12−Deoxyroyleanone−81.7−72.8no dock−67.2−77.2
9α,13α− epi−Dioxyabiet−8(14)−en−18−oic acid−90.4−73.1no dock−68.7−77.1
9α,13α− epi−Dioxyabiet−8(14)en−18−ol−80.3−70.1no dock−65.9−72.3
Dracocephalone A−83.2−64.1no dock−76.6−82.5
Dracocequinone A−82.5−63.6no dock−77.7−74.9
Dracocequinone B−85.6−69.1no dock−76.4−75.5
Ferruginol−78.9−71.0no dock−73.2−79.0
Hinokiol−77.7−68.5no dock−62.4−70.0
Hinokiol−1−one−84.6−69.6no dock−72.9−72.4
7β−Hydroxyabieta−8,13−diene−11,12−dione−85.1−71.6no dock−73.0−85.6
7α−Hydroxyabieta−8,11,13−triene−79.5−68.9no dock−67.6−77.1
14−Hydroxy−7,9(11),13−abietatriene−6,12−dione−82.9−71.7no dock−71.5−84.5
11−Hydroxy−7,9(11),13−abietatrien−12−one−81.1−68.0no dock−69.6−73.3
12−Hydroxy−8,12−abietadiene−3,11,14−trione−83.4−76.4no dock−73.8−86.9
1β−Hydroxycryptotanshinone−84.1−66.5no dock−75.5−88.2
7−Hydroxy−12−methoxy−20− nor−abieta−1,5(10),7,9,12−pentaen−6,14−dione−84.6−67.7no dock−73.0−78.3
14−Hydroxy−6−oxoferruginol−85.2−73.0no dock−71.7−79.3
6−Hydroxysalvinolone−81.2−68.6no dock−80.7−85.5
Komarovinone A−86.9−66.3no dock−74.9−84.7
1−Oxocryptotanshinone−83.9−66.9no dock−72.6−84.1
1−Oxomiltirone−85.5−64.4no dock−69.7−78.6
Royleanone−82.6−72.0no dock−72.8−82.1
Sugiol−81.8−70.4no dock−72.6−78.7
Taxodione−81.2−68.2no dock−71.1−75.8
6,11,12,16−Tetrahydroxy−5,8,11,13−abietatetraen−7−one−88.5−66.5no dock−85.7−93.8
6,12,14−Trihydroxyabieta−5,8,11,13−tetraen−7−one−83.5−73.4no dock−75.9−81.9
4− epi−Triptobenzene L−83.0−72.3no dock−65.2−76.3
Uncinatone−93.0−73.3no dock−82.5−85.5
Table 19. MolDock docking energies (kJ/mol) of clerodane diterpenoids with Leishmania major protein targets.
Table 19. MolDock docking energies (kJ/mol) of clerodane diterpenoids with Leishmania major protein targets.
Clerodane diterpenoidsLmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLdonNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
15−Acetoxy−cis−cleroden−3−en−18−al−68.6−94.1−85.0−97.9−96.0−87.3−90.4−94.9−94.7−107.1−92.6−106.9
15−Acetoxy−cis−cleroden−3−en−18−oic acid−75.0−103.1−88.3−97.2−92.3−87.0−91.6−95.3−93.2−97.7−94.4−97.3
18−Acetoxy−cis−cleroden−3−en−15−oic acid−76.9−103.7−82.7−96.7−88.8−80.7−97.3−96.8−89.3−104.2−97.5−98.2
15−O−Acetylcistadiol−68.0−94.7−87.4−97.3−94.7−80.4−96.8−89.2−92.9−106.7−95.0−95.3
18−O−Acetylcistadiol−70.5−103.4−88.1−91.7−93.2−85.0−94.0−93.8−82.3−101.2−95.9−100.3
Cistadiol−64.1−93.4−79.7−81.6−81.9−69.0−77.1−85.2−79.2−78.9−80.7−92.5
trans−Dehydrocrotonin−78.6−114.9−90.2−91.8−84.5−75.9−89.0−89.1−99.2−115.1−97.7−92.1
15,18−Di−O−acetylcistadiol−77.8−100.5−92.8−109.4−94.8−84.2−90.5−107.0−91.6−117.5−100.6−110.4
8−epi−Kolavenol−71.5−94.5−79.2−80.4−85.0−72.3−78.7−80.6−82.8−92.9−85.3−95.3
epi−Populifolic acid−69.9−85.5−72.7−82.3−83.4−71.7−76.3−82.2−78.3−85.0−78.2−89.9
ent−16R−Hydroxy−3,13−clerodadien−15,16−olide−77.7−108.7−86.4−88.2−87.7−88.2−90.8−87.5−101.9−105.9−104.9−97.4
ent−16S−Hydroxy−3,13−clerodadien−15,16−olide−81.9−101.9−84.6−91.0−83.9−78.4−93.4−82.2−100.3−110.7−99.4−105.1
15−Hydroxy−cis−cleroden−3−en−18−al−66.5−91.8−77.4−81.8−86.8−76.7−76.8−83.7−77.5−92.8−80.1−91.4
15−Hydroxy−cis−cleroden−3−en−18−oic acid−69.0−95.8−90.1−83.5−86.9−80.5−82.1−86.0−80.4−95.9−84.3−95.2
18−Hydroxy−cis−cleroden−3−en−15−oic acid−70.0−93.4−76.1−86.3−86.8−76.2−79.7−87.2−81.1−96.1−82.9−97.4
ent−12−Oxo−3,13(16)−clerodien−15−oic acid−75.0−112.7−86.3−90.0−93.2−88.2−87.7−83.0−96.5−107.2−87.6−110.5
Table 20. MolDock docking energies (kJ/mol) of clerodane diterpenoids with Leishmania donovani and L. mexicana protein targets.
Table 20. MolDock docking energies (kJ/mol) of clerodane diterpenoids with Leishmania donovani and L. mexicana protein targets.
Clerodane diterpenoidsLdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
Site 1Site 2Site 3
15−Acetoxy−cis−cleroden−3−en−18−al−80.4−84.1−75.1−87.3−76.7−107.2−75.4−101.2−96.3−96.5−89.3−84.6
15−Acetoxy−cis−cleroden−3−en−18−oic acid−83.5−85.0−75.2−87.0−86.3−93.6−84.4−104.8−100.2−92.9−90.4−80.9
18−Acetoxy−cis−cleroden−3−en−15−oic acid−82.9−90.6−85.1−80.7−77.3−109.2−77.6−97.4−95.9−90.8−89.5−95.5
15−O−Acetylcistadiol−82.8−79.6−72.7−80.4−77.4−102.7−77.8−98.9−96.3−96.8−87.7−89.7
18−O−Acetylcistadiol−79.8−92.7−66.9−85.0−73.2−105.6−78.9−97.1−92.5−96.8−92.6−98.6
Cistadiol−66.6−81.0−58.3−69.0−70.5−91.1−70.4−88.0−90.4−82.8−82.5−80.2
trans−Dehydrocrotonin−92.8−98.7−51.3−75.9−73.0−100.5−77.1−94.2−107.8−87.6−92.4−95.2
15,18−Di−O−acetylcistadiol−82.2−82.4−94.8−84.2−85.2−122.2−86.7−104.1−102.9−101.7−97.4−99.1
8−epi−Kolavenol−75.5−83.0−77.8−72.3−71.7−100.8−70.6−85.6−92.1−84.2−94.6−78.9
epi−Populifolic acid−68.3−75.8−63.4−71.7−73.8−89.4−69.7−88.7−91.1−79.3−85.0−82.4
ent−16R−Hydroxy−3,13−clerodadien−15,16−olide−74.7−89.1−82.9−88.2−85.4−105.8−79.8−96.5−103.1−89.0−95.5−83.1
ent−16S−Hydroxy−3,13−clerodadien−15,16−olide−88.6−91.8−82.7−78.4−83.9−100.1−81.3−97.2−102.0−92.3−90.3−85.8
15−Hydroxy−cis−cleroden−3−en−18−al−77.5−87.9−67.4−76.7−74.1−97.2−70.9−87.6−96.8−86.4−85.4−82.4
15−Hydroxy−cis−cleroden−3−en−18−oic acid−71.4−86.4−66.4−80.5−74.9−99.5−73.3−85.9−99.3−88.1−88.5−80.5
18−Hydroxy−cis−cleroden−3−en−15−oic acid−72.5−84.3−59.0−76.2−78.2−95.4−73.2−90.2−89.2−83.9−90.5−88.0
ent−12−Oxo−3,13(16)−clerodien−15−oic acid−84.3−95.2−72.0−88.2−85.3−88.0−76.6−95.9−108.8−88.3−91.6−86.9
Table 21. MolDock docking energies (kJ/mol) of clerodane and labdane diterpenoids with Leishmania infantum protein targets.
Table 21. MolDock docking energies (kJ/mol) of clerodane and labdane diterpenoids with Leishmania infantum protein targets.
Clerodane diterpenoidsLinfCYP51LinfGLO2LinfPnC1LinfTDR1LinfTR
15−Acetoxy−cis−cleroden−3−en−18−al−96.8−78.2no dock−90.4−91.8
15−Acetoxy−cis−cleroden−3−en−18−oic acid−93.0−82.7no dock−87.6−91.7
18−Acetoxy−cis−cleroden−3−en−15−oic acid−98.2−78.1no dock−87.6−97.6
15−O−Acetylcistadiol−101.7−89.8no dock−88.4−94.3
18−O−Acetylcistadiol−95.8−78.3no dock−88.4−93.8
Cistadiol−86.8−68.7no dock−78.3−82.2
trans−Dehydrocrotonin−89.6−74.5no dock−77.6−88.9
15,18−Di−O−acetylcistadiol−95.6−85.8no dock−89.2−103.5
8−epi−Kolavenol−83.6−72.3−18.2−80.5−78.8
epi−Populifolic acid−83.8−71.4no dock−75.9−77.0
ent−16R−Hydroxy−3,13−clerodadien−15,16−olide−87.9−75.1−22.6−83.9−87.5
ent−16S−Hydroxy−3,13−clerodadien−15,16−olide−88.4−67.5no dock−79.6−78.8
15−Hydroxy−cis−cleroden−3−en−18−al−83.0−68.9no dock−81.0−81.2
15−Hydroxy−cis−cleroden−3−en−18−oic acid−89.4−66.8no dock−78.4−78.1
18−Hydroxy−cis−cleroden−3−en−15−oic acid−87.5−69.6−31.7−82.8−81.3
Labdane diterpenoids
ent−3β−Acetoxy−13−epi−manoyl−oxide−94.3−72.4no dock−67.4−88.0
Andrographolide−97.9−80.4no dock−81.1−91.9
14(R)−Aulacocarpin C
14(S)−Aulacocarpin C−93.1−81.7no dock−81.7−92.8
Aulacocarpin D−92.7−74.5no dock−85.8−93.5
trans−Communic acid−90.8−75.0no dock−82.6−91.6
trans−Communic acid methyl ester−84.3−77.2no dock−76.0−82.7
Copalic acid−89.8−74.8no dock−72.8−86.8
Dehydropinifolic acid 15−methyl ester−93.9−84.1no dock−78.1−83.6
12(S)−Hydroxy−15(R)−methoxy−labdan−8(17),13(14)−dien−15,16−olide−93.3−84.8no dock−89.8−93.5
12(S)−Hydroxy−15(S)−methoxy−labdan−8(17,)13(14)−dien−15,16−olide−99.3−88.5no dock−88.8−95.1
Labda−8(17),12−diene−15,16−dial−94.2−84.8no dock−89.2−100.2
13(E)−Labda−7,13−dien−8α,15−diol−87.7−76.3no dock−81.7−86.6
Labda−12,14−dien−7α,8α−diol−89.1−77.8no dock−79.8−88.4
Labdan−8α,15−diol−85.9−77.1no dock−76.1−87.2
Labd−8(17)−en−3β,15−diol−85.8−77.4no dock−82.0−90.2
13(E)−Labd−13−en−8α,15−diol−84.2−76.9no dock−79.7−87.2
Lambertianic acid−87.0−75.4no dock−78.4−83.4
15(R)−Methoxy−labdan−8(17),11(E),13(14)−trien−15,16−olide−90.0−73.6no dock−72.5−89.3
15(S)−Methoxy−labdan−8(17),11(E),13(14)−trien−15,16−olide−94.2−87.8no dock−88.3−92.3
ent−12−Oxo−8,13(16)−labdadien−15−oic acid−96.0−86.3no dock−85.3−96.8
ent−3β−Acetoxy−13−epi−manoyl−oxide−94.1−77.8no dock−78.5−88.9
Table 22. MolDock docking energies (kJ/mol) of labdane diterpenoids with Leishmania major protein targets.
Table 22. MolDock docking energies (kJ/mol) of labdane diterpenoids with Leishmania major protein targets.
Labdane diterpenoidsLmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLdonNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
ent−3β−Acetoxy−13−epi−manoyl−oxide−74.9−96.4−76.3−82.2−82.7−78.7−90.7−82.0−89.0−85.9−80.1−91.2
Andrographolide−86.7−114.6−90.5−92.1−96.5−101.8−98.5−94.4−101.6−114.1−97.7−95.9
14(R)−Aulacocarpin C−74.4−116.1−85.2−91.7−97.7−99.7−95.7−85.2−98.1−107.0−91.8−103.3
14(S)−Aulacocarpin C−83.6−114.7−88.3−90.3−91.7−97.4−90.6−83.1−99.9−107.9−94.0−100.3
Aulacocarpin D−80.8−108.3−89.0−87.3−87.3−86.0−91.8−98.6−92.9−108.3−93.8−98.9
trans−Communic acid−69.5−109.4−86.3−86.7−87.5−89.7−83.7−84.0−88.4−97.1−88.2−88.3
trans−Communic acid methyl ester−81.3−103.5−84.7−86.3−85.6−84.1−85.7−83.0−92.3−99.6−89.8−88.7
Copalic acid−69.5−102.7−88.4−89.5−83.2−83.9−86.0−96.2−90.1−105.1−93.9−104.6
Dehydropinifolic acid 15−methyl ester−87.3−116.3−102.2−90.1−87.9−91.3−101.0−89.8−89.7−104.1−99.8−103.3
12(S)−Hydroxy−15(R)−methoxy−labdan−8(17),13(14)−dien−15,16−olide−85.8−114.5−87.2−97.5−88.7−93.8−96.4−88.0−96.1−108.9−103.0−110.1
12(S)−Hydroxy−15(S)−methoxy−labdan−8(17,)13(14)−dien−15,16−olide−90.2−112.6−89.4−98.7−98.8−84.0−107.3−89.1−91.2−110.4−103.6−111.4
Labda−8(17),12−diene−15,16−dial−77.5−107.2−87.2−82.9−93.0−95.8−82.8−89.0−97.5−103.2−95.5−102.8
13(E)−Labda−7,13−dien−8α,15−diol−76.9−100.6−85.8−87.0−86.3−89.7−100.7−85.8−87.9−107.5−91.0−90.8
Labda−12,14−dien−7α,8α−diol−71.9−99.4−76.2−75.8−89.8−89.8−90.5−85.1−81.5−101.3−87.8−94.7
Labdan−8α,15−diol−78.9−101.4−84.6−81.5−80.3−92.1−93.7−82.7−86.0−108.6−83.9−92.3
Labd−8(17)−en−3β,15−diol−75.5−106.7−82.2−82.9−80.6−71.0−88.0−81.0−93.9−104.9−85.9−90.8
13(E)−Labd−13−en−8α,15−diol−69.4−105.0−82.1−83.3−85.1−89.1−88.5−85.8−88.9−107.8−89.8−92.2
Lambertianic acid−69.8−110.5−86.3−82.0−84.0−79.8−81.8−83.9−93.5−100.7−87.7−88.9
15(R)−Methoxy−labdan−8(17),11(E),13(14)−trien−15,16−olide−88.3−111.4−84.5−97.3−91.3−91.7−104.9−94.4−91.8−101.5−95.0−98.9
15(S)−Methoxy−labdan−8(17),11(E),13(14)−trien−15,16−olide−83.1−104.7−84.8−89.0−95.4−88.5−109.2−98.3−99.0−106.2−98.3−97.3
ent−12−Oxo−8,13(16)−labdadien−15−oic acid−78.0−107.7−93.4−92.3−88.2−92.1−90.6−90.0−94.1−100.0−97.0−100.4
Table 23. MolDock docking energies (kJ/mol) of labdane diterpenoids with Leishmania donovani and L. mexicana protein targets.
Table 23. MolDock docking energies (kJ/mol) of labdane diterpenoids with Leishmania donovani and L. mexicana protein targets.
LdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
Labdane diterpenoidsSite 1Site 2Site 3
ent−3β−Acetoxy−13−epi−manoyl−oxide−83.3−77.6−60.4−78.7−67.9−94.4−69.1−86.9−90.2−84.0−77.7−78.3
Andrographolide−88.9−93.2−94.9−101.8−86.1−114.0−79.6−100.7−110.3−100.3−107.0−95.5
14(R)−Aulacocarpin C−87.0−98.3−92.5−99.7−78.4−103.3−76.8−95.7−99.6−91.7−114.0−84.2
14(S)−Aulacocarpin C−85.6−95.6−90.3−97.4−75.0−100.7−77.8−90.6−97.1−95.8−109.0−86.7
Aulacocarpin D−96.6−88.1−75.2−86.0−87.6−99.9−73.6−87.5−95.9−89.8−88.3−87.8
trans−Communic acid−77.9−87.9−79.6−89.7−70.6−100.8−75.8−88.3−92.3−82.9−98.3−83.1
trans−Communic acid methyl ester−85.8−90.8−81.9−84.1−73.5−104.8−72.2−88.1−95.4−82.4−90.0−85.2
Copalic acid−89.0−92.6−85.1−83.9−73.8−90.3−76.9−92.0−94.8−88.0−92.4−97.5
Dehydropinifolic acid 15−methyl ester−85.8−95.2−88.4−91.3−84.5−123.2−85.7−100.6−111.6−93.2−104.2−99.0
12(S)−Hydroxy−15(R)−methoxy−labdan−8(17),13(14)−dien−15,16−olide−92.1−93.8−90.8−93.8−75.2−117.2−79.4−101.2−117.2−96.5−104.7−93.8
12(S)−Hydroxy−15(S)−methoxy−labdan−8(17,)13(14)−dien−15,16−olide−95.4−92.4−82.7−84.0−88.1−116.2−91.2−103.1−117.1−92.4−109.7−93.1
Labda−8(17),12−diene−15,16−dial−90.6−93.4−85.7−95.8−75.4−97.3−72.3−93.0−97.0−87.4−99.5−85.4
13(E)−Labda−7,13−dien−8α,15−diol−88.4−82.3−80.9−89.7−76.3−109.7−73.5−87.1−100.2−82.1−93.7−88.8
Labda−12,14−dien−7α,8α−diol−86.9−83.8−80.5−89.8−77.9−86.3−78.7−89.2−100.4−85.5−91.2−91.6
Labdan−8α,15−diol−86.8−82.0−82.5−92.1−73.2−94.9−76.4−95.9−93.7−86.0−90.8−88.8
Labd−8(17)−en−3β,15−diol−78.5−85.4−86.9−71.0−71.0−87.8−72.0−93.5−97.3−81.6−93.8−86.2
13(E)−Labd−13−en−8α,15−diol−81.4−82.1−77.1−89.1−71.9−104.1−83.4−88.7−99.2−84.5−92.7−92.0
Lambertianic acid−82.2−82.9−81.6−79.8−72.9−109.5−75.1−95.1−96.2−85.6−98.4−80.3
15(R)−Methoxy−labdan−8(17),11(E),13(14)−trien−15,16−olide−106.6−91.2−92.5−91.7−79.3−121.2−76.7−97.1−105.9−94.3−95.6−91.2
15(S)−Methoxy−labdan−8(17),11(E),13(14)−trien−15,16−olide−92.3−92.2−93.3−88.5−87.3−115.8−78.5−94.5−101.8−97.0−89.2−91.5
ent−12−Oxo−8,13(16)−labdadien−15−oic acid−76.2−84.3−84.0−92.1−89.2−99.0−72.6−102.2−105.2−91.1−103.5−91.8
Table 24. MolDock docking energies (kJ/mol) of kaurane and pimarane diterpenoids with Leishmania major protein targets.
Table 24. MolDock docking energies (kJ/mol) of kaurane and pimarane diterpenoids with Leishmania major protein targets.
Kaurane diterpenoidsLmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLdonNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
15−Angeloyl−4α,15β−kaur−16−en−18−oic acid −88.6−116.3−75.8−97.5−97.3−78.2−85.5−98.6−97.4−116.0−91.4−106.3
ent−11α−Hydroxy−16−kauren−15−one−64.3−98.8−69.7−76.7−83.3−64.7−87.8−83.0−74.0−85.7−75.1−81.0
Kaurenoic acid−70.4−95.2−77.8−76.3−81.4−58.4−86.5−80.6−89.7−97.5−75.5−83.2
Perymenic acid−97.6−115.4−75.2−95.4−103.0−81.2−88.9−99.6−98.5−118.4−91.2−103.7
ent−15β−Senecioyloxy−16,17−epoxy−kauran−18−oic acid−97.3−120.5−76.6−93.6−102.4−87.8−100.7−100.8−86.6−111.7−93.3−104.6
Pimarane diterpenoids
Acanthoic acid−66.0−97.0−73.1−84.0−86.6−72.3−87.9−81.1−78.7−87.9−72.7−82.5
7β−Hydroxy− ent−pimara−8(14),15−dien−19−oic acid−74.0−93.7−79.3−84.3−87.3−71.7−92.6−87.7−76.7−87.6−78.9−81.2
ent−15−Pimarene−8β,19−diol−72.1−97.1−69.0−78.0−86.3−66.1−87.4−79.1−77.5−84.4−74.3−85.5
ent−8(14),15−Pimaradien−3β−acetoxy−72.5−85.3−83.9−90.3−89.4−71.7−88.6−82.1−83.7−99.7−88.9−92.1
ent−8(14),15−Pimaradien−3β,19−diol−66.9−90.8−66.2−78.3−91.3−71.5−83.3−80.0−75.0−86.6−80.9−81.6
ent−Pimara−8(14),15−dien−19−oic acid−65.8−91.7−69.9−81.3−87.1−70.6−89.3−80.2−81.5−85.7−75.7−77.4
ent−8(14),15−Pimaradien−3β−ol−64.7−89.0−66.5−77.7−86.2−66.6−82.3−76.4−73.8−79.4−81.8−76.4
Table 25. MolDock docking energies (kJ/mol) of kaurane and pimarane diterpenoids with Leishmania donovani and L. mexicana protein targets.
Table 25. MolDock docking energies (kJ/mol) of kaurane and pimarane diterpenoids with Leishmania donovani and L. mexicana protein targets.
LdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
Kaurane diterpenoidsSite 1Site 2Site 3
15−Angeloyl−4α,15β−kaur−16−en−18−oic acid −97.4−78.7−27.8−78.2−91.8−121.4−75.9−96.9−104.0−89.2−92.8−77.3
ent−11α−Hydroxy−16−kauren−15−one−66.2−82.3no dock−64.7−61.9−84.4−63.0−81.1−79.6−73.8−70.1−80.5
Kaurenoic acid−69.6−73.9−21.6−58.4−64.6−88.8−64.5−80.3−93.9−77.4−81.3−78.1
Perymenic acid−100.6−92.3−45.0−81.2−85.7−128.3−76.8−100.4−99.7−95.7−91.9−80.3
ent−15β−Senecioyloxy−16,17−epoxy−kauran−18−oic acid−99.1−88.1−38.0−87.8−90.1−128.9−77.2−96.5−99.3−92.9−98.0−81.1
Pimarane diterpenoids
Acanthoic_acid−69.3−79.7−62.5−72.3−59.8−90.8−69.0−81.5−92.4−79.2−78.3−79.4
7β−Hydroxy− ent−pimara−8(14),15−dien−19−oic acid−71.2−78.8−13.1−71.7−71.7−101.0−68.7−88.0−96.6−83.5−76.9−71.3
ent−15−Pimarene−8β,19−diol−75.9−77.9−63.4−66.1−72.6−85.2−68.6−79.0−79.7−80.1−71.6−79.0
ent−8(14),15−Pimaradien−3β−acetoxy−79.6−80.5−36.8−71.7−71.4−90.2−63.2−83.7−88.7−84.4−73.5−76.4
ent−8(14),15−Pimaradien−3β,19−diol−67.6−73.6−31.7−71.5−65.3−90.2−69.2−83.6−95.0−79.6−73.6−82.7
ent−Pimara−8(14),15−dien−19−oic acid−66.6−77.7−53.0−70.6−64.0−94.0−66.0−85.4−88.0−79.7−70.8−77.1
ent−8(14),15−Pimaradien−3b−ol−69.3−71.6−26.5−66.6−63.1−88.7−64.5−80.7−94.3−77.1−72.6−79.9
Table 26. MolDock docking energies (kJ/mol) of miscellaneous diterpenoids with Leishmania major protein targets.
Table 26. MolDock docking energies (kJ/mol) of miscellaneous diterpenoids with Leishmania major protein targets.
LmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLdonNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
Cassane diterpenoids
6β− O−Cinnamoyl−12−hydroxy−(13)15−en−16,12−olide−18−cassaneoic acid−78.8−123.0−110.4−111.0−119.5−108.1−107.4−108.1−120.0−134.4−115.8−116.4
6α,7β−Diacetoxyvouacapane−77.8−118.7−80.7−91.0−92.6−74.7−85.6−99.8−86.5−90.4−88.3−88.0
6β− O−2'3'−Dihydrocinnamoyl−12−hydroxy−(13)15−en−16,12−olide−18−cassaneoic acid−107.0−125.0−97.1−107.3−121.6−101.3−109.0−109.0−117.3−135.2−115.1−114.3
Icetaxane diterpenoids
Cyclocoulterone−70.3−92.1−83.7−88.6−78.7−81.3−86.7−96.1−91.6−100.2−91.8−92.0
5− epi−Icetexone−80.9−91.0−74.2−81.6−88.3−27.2−95.7−88.5−88.5−96.9−98.8−85.9
Komaroviquinone−75.7−83.0−87.6−84.9−75.6−76.5−90.9−98.1−97.8−105.2−87.8−87.0
Mulinane diterpenoids
Azorellanol−64.7−107.8−74.6−79.1−98.7−80.0−94.5−99.7−85.3−98.6−88.5−91.9
7−Deacetylazorellanol−72.5−98.4−72.3−80.2−79.0−72.4−88.9−91.8−76.2−94.0−90.1−78.7
Mulin−11,13−dien−20−oic acid−83.1−103.0−78.0−84.3−80.7−71.5−87.5−83.5−87.0−100.5−88.1−88.3
Mulinic acid−69.4−98.9−71.9−82.4−80.7−82.3−83.6−85.7−74.6−93.7−78.3−97.0
Mulinolic acid−75.6−94.5−87.3−82.5−84.5−85.1−84.9−90.2−81.1−102.3−92.2−88.7
Miscellaneous diterpenoids
Hypoestoxide−74.1−117.7−88.3−80.1−87.8−85.2−94.0−97.0−78.1−81.1−99.5−99.2
Komarovispirone−74.1−92.9−75.8−88.9−90.5−75.5−85.4−86.4−75.3−79.9−94.0−91.4
Sacculatal−69.5−112.7−85.2−87.1−86.1−82.4−88.0−85.9−104.4−103.5−95.2−100.4
Serratol−69.2−90.5−75.7−77.2−78.8−77.4−82.1−89.7−79.1−93.2−90.3−88.6
Totarol−62.7−96.6−64.9−85.1−76.4−69.8−89.2−80.7−74.6−97.7−77.8−93.1
Table 27. MolDock docking energies (kJ/mol) of miscellaneous diterpenoids with Leishmania donovani and L. mexicana protein targets.
Table 27. MolDock docking energies (kJ/mol) of miscellaneous diterpenoids with Leishmania donovani and L. mexicana protein targets.
Cassane diterpenoidsLdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
Site 1Site 2Site 3
6β− O−Cinnamoyl−12−hydroxy−(13)15−en−16,12−olide−18−cassaneoic acid−107.7−94.7−104.3−108.1−103.7−126.5−103.9−136.7−133.4−117.8−110.2−91.8
6α,7β−Diacetoxyvouacapane−83.2−82.4−78.8−74.7−77.3−99.7−86.4−103.6−102.4−86.7−85.6−81.5
6β− O−2'3'−Dihydrocinnamoyl−12−hydroxy−(13)15−en−16,12−olide−18−cassaneoic acid−108.6−100.4−52.6−101.3−97.7−125.8−92.8−140.1−130.8−118.5−109.0−102.6
Icetaxane diterpenoids
Cyclocoulterone−89.0−82.5−71.2−81.3−78.1−117.3−70.7−87.7−98.4−87.3−83.5−79.3
5− epi−Icetexone−90.5−80.3−85.1−27.2−75.6−99.1−68.4−89.5−88.3−78.6−80.3−80.3
Komaroviquinone−75.5−81.9−77.6−76.5−72.6−105.7−73.9−90.4−92.8−82.4−81.2−69.5
Mulinane diterpenoids
Azorellanol−80.6−82.6−87.2−80.0−71.4−100.2−77.7−95.1−100.2−89.9−94.0−84.8
7−Deacetylazorellanol−73.7−90.1−81.0−72.4−75.4−103.4−72.2−91.8−88.7−82.8−89.1−72.3
Mulin−11,13−dien−20−oic acid−84.7−95.2−85.0−71.5−71.3−97.5−72.5−98.2−99.2−80.6−92.2−86.8
Mulinic acid−63.1−93.4−72.3−82.3−70.2−98.9−63.7−85.5−94.4−77.2−87.1−83.0
Mulinolic acid−76.7−95.1−77.5−85.1−78.7−105.7−68.8−94.1−94.7−80.4−87.4−82.6
Miscellaneous diterpenoids
Hypoestoxide−80.6−92.1−67.1−85.2−78.1−94.9−85.7−114.8−102.4−79.6−87.9−72.7
Komarovispirone−77.7−80.5−67.4−75.5−70.3−101.0−77.5−90.5−92.3−86.1−80.8−79.0
Sacculatal−86.4−84.1−84.0−82.4−77.2−103.5−78.1−92.5−104.3−87.9−98.7−79.1
Serratol−67.7−78.7−59.5−77.4−67.0−89.9−71.4−94.3−92.3−82.9−90.1−70.1
Totarol−63.9−70.3−59.4−69.8−60.5−88.0−68.6−84.0−81.5−72.2−90.4−65.7
Table 28. MolDock docking energies (kJ/mol) of miscellaneous diterpenoids with Leishmania infantum protein targets.
Table 28. MolDock docking energies (kJ/mol) of miscellaneous diterpenoids with Leishmania infantum protein targets.
Kaurane diterpenoidsLinfCYP51LinfGLO2LinfPnC1LinfTDR1LinfTR
15−Angeloyl−4α,15β−kaur−16−en−18−oic acid −97.4−64.6no dock−82.4−95.6
ent−11α−Hydroxy−16−kauren−15−one−82.8−66.5no dock−66.5−76.6
Kaurenoic acid−79.9−65.8no dock−77.4−82.6
Perymenic acid−98.3−77.0no dock−83.2−97.0
ent−15β−Senecioyloxy−16,17−epoxy−kauran−18−oic acid−99.6−77.9no dock−85.4−102.2
Pimarane diterpenoids
Acanthoic_acid−83.6−64.6no dock−72.4−82.6
7β−Hydroxy− ent−pimara−8(14),15−dien−19−oic acid−90.4−67.2no dock−75.0−79.2
ent−15−Pimarene−8β,19−diol−84.0−63.8no dock−69.9−77.4
ent−8(14),15−Pimaradien−3β−acetoxy−90.6−73.3no dock−70.5−92.1
ent−8(14),15−Pimaradien−3β,19−diol−82.2−69.2no dock−67.0−78.9
ent−Pimara−8(14),15−dien−19−oic acid−84.2−69.0no dock−70.8−80.3
ent−8(14),15−Pimaradien−3b−ol−78.3−67.2no dock−66.8−79.1
Cassane diterpenoids
6β− O−Cinnamoyl−12−hydroxy−(13)15−en−16,12−olide−18−cassaneoic acid−125.4−91.1no dock−105.3−119.8
6α,7β−Diacetoxyvouacapane−93.8−77.7no dock−83.7−93.9
6β− O−2'3'−Dihydrocinnamoyl−12−hydroxy−(13)15−en−16,12−olide−18−cassaneoic acid−124.7−88.7no dock−99.0−114.1
Icetaxane diterpenoids
Cyclocoulterone−90.3−68.7no dock−76.9−90.0
5− epi−Icetexone−99.1−75.8no dock−81.0−81.6
Komaroviquinone−96.8−72.4no dock−75.6−88.7
Mulinane diterpenoids
Azorellanol−99.1−72.4no dock−78.2−91.2
7−Deacetylazorellanol−88.5−71.4no dock−76.5−85.9
Mulin−11,13−dien−20−oic acid−87.5−72.9no dock−79.1−78.6
Mulinic acid−88.3−70.6no dock−73.8−84.3
Mulinolic acid−89.0−78.1no dock−78.6−85.8
Miscellaneous diterpenoids
Hypoestoxide−97.2−82.2no dock−73.6−91.2
Komarovispirone−83.1−72.0no dock−74.4−79.9
Sacculatal−93.5−77.7no dock−84.4−88.1
Serratol−81.7−77.1no dock−78.5−78.5
Totarol−76.4−67.7no dock−67.9−73.4
Over 100 antiparasitic diterpenoids were docked into the protein targets in this study. These include abietane-, clerodane-, kaurane-, labdane-, pimarane-, cassane- and mulinane-like diterpenoids. In general, diterpenoids preferentially dock to LmajMetRS, LmajDHODH and LmexGPDH. 12-O-deacetyl-6-O-acetyl-18-acetyloxycoleon Q, the antiplasmodial diterpene isolated from the tropical Asia plant Anisochilus harmandii (Lamiaceae) [64] has a stronger docking energy (−111.8 kJ/mol) for LmajPDE1 than the co-crystallized competitive phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (docking energy = −78.1 kJ/mol). 14(R)-Aulacocarpin C and 15(S)-methoxy-labdan-8(17),11(E),13(14)-trien-15,16-olide are also selective for LmexPYK and LmajOPB, respectively. The cassane-like antileishmanial diterpenes 6β-O-2'3'-dihydrocinnamoyl-12-hydroxy-(13)15-en-16,12-olide-18-cassaneoic acid and 6β-O-cinnamoyl-12-hydroxy-(13)15-en-16,12-olide-18-cassaneoic acid have stronger docking energies than any of the other docked diterpenoids for most of the protein targets. These higher docking energies correlate with the fact they have higher molecular weights that the other diterpenoids. Despite the molecular weight correlation, 6β-O-2'3'-dihydrocinnamoyl-12-hydroxy-(13)15-en-16,12-olide-18-cassaneoic acid (MW: 496.592) is selective for LmajNMT. The compound’s docking score for LmajNMT is comparable to that of the protein’s co-crystallized pyrazole sulfonamide inhibitor (PDB ID: 4a30; MW: 495.425; docking energy = −121.1 kJ/mol). The lowest energy pose of 6β-O-2'3'-dihydrocinnamoyl-12-hydroxy-(13)15-en-16,12-olide-18-cassaneoic acid is predicted to have extensive interactions with residues Ala 204, Asp 83, Asp 84, Glu 82, Gly 205, Phe 88, Phe 90, Tyr 217, Tyr 345, Val 81 and Val 206. The cassane diterpenoid is predicted to have hydrogen bonding interactions through its carboxylic acid moiety and the ester bond of its cinnamoyl substituent to the backbone carbonyl group of Gly 205, and the side chain phenolic residue of Tyr 217, respectively (Figure 19). The icetaxane diterpenoids 5-epi-icetaxone showed preferential docking to L. infantum sterol 14α-demethylase (LinfCYP51) with a lower docking energy than the co-crystallized ligand, fluconazole (−99.1 and −91.3 kJ/mol, respectively).
Figure 19. The lowest-energy pose of 6β-O-2'3'-dihydrocinnamoyl-12-hydroxy-(13)15-en-16,12-olide-18-cassaneoic acid and LmajNMT. The hydrogen bonding interactions between the ligand and the protein (Gly 205 and Tyr 217) is shown as blue dash lines. Val 81, Asp 83 and Phe 88 were also predicted to have very strong steric interactions with the ligand.
Figure 19. The lowest-energy pose of 6β-O-2'3'-dihydrocinnamoyl-12-hydroxy-(13)15-en-16,12-olide-18-cassaneoic acid and LmajNMT. The hydrogen bonding interactions between the ligand and the protein (Gly 205 and Tyr 217) is shown as blue dash lines. Val 81, Asp 83 and Phe 88 were also predicted to have very strong steric interactions with the ligand.
Molecules 18 07761 g019

2.4. Triterpenoid Docking

Triterpenoids, including limonoids, withanolides, quassinoids, and steroids are shown in Figure 20, Figure 21, Figure 22, Figure 23, and Figure 24. The docking energies for the triterpenoid-based ligands are compiled in Table 29, Table 30, Table 31, Table 32, Table 33, Table 34, Table 35, Table 36, Table 37, Table 38, Table 39 and Table 40. The triterpenoids ligands with the strongest docking energies were the limonoids carapolide A and khayanolide A, and the withanolides 24,25-epoxywithanolide D and withangulatin A. Carapolide A showed significant docking to LmajDHODH (docking energy = −140.0 kJ/mol). Khayanolide A preferentially docked with LmajMetRS and LmexGPDH (docking energies = −138.5 and −137.8 kJ/mol, respectively). The limonoid with the strongest docking was, however, grandifotane with LmajDHODH with a docking energy of −154.4 kJ/mol. 6-O-Acetylswietenolide docked strongly to LmexGPDH (docking energy = −142.7 kJ/mol). The withanolide with the strongest docking was physagulin F with LmajMetRS, which had a docking energy of −133.2 kJ/mol. As a class, the steroids showed the most target selectivity with six of the seven steroids significantly docking more strongly to LmajMetRS. In general, limonoids showed some selectivity for LmexGPDH and LmajDHODH, while withanolides docked more selectively with LmajUGPase.
Figure 20. Triterpenoids examined in this work.
Figure 20. Triterpenoids examined in this work.
Molecules 18 07761 g020
Figure 21. Steroids examined in this work.
Figure 21. Steroids examined in this work.
Molecules 18 07761 g021
Figure 22. Quassinoids examined in this work.
Figure 22. Quassinoids examined in this work.
Molecules 18 07761 g022
Figure 23. Limonoids examined in this work.
Figure 23. Limonoids examined in this work.
Molecules 18 07761 g023
Figure 24. Withanolides examined in this work.
Figure 24. Withanolides examined in this work.
Molecules 18 07761 g024
Grandifotane showed selective docking to LmajDHODH with a docking energy of −154.4 kJ/mol. The lowest-energy pose of the ligand placed the compound at the binding site of the co-crystallized ligand, 5-nitroorotic acid (Figure 25). The furan ring of the ligand is sandwiched between the riboflavin monophosphate cofactor and Cys 131. There are hydrogen-bonding interactions between the docked ligand and residues Asn 199, Asn 68, Ser 69, and Ser 130. Grandifotane, isolated from Khaya grandifoliola [65], has apparently not been reported to be antiparasitic. The bark and seeds of K. grandifoliola, however, have shown significant antimalarial activity [66]. 6-O-Acetylswietenolide, also isolated from K. grandifoliola, has shown antiplasmodial activity [67], and this compound showed preferential docking to LmexGPDH. The lowest-energy docking pose of 6-O-acetylswietenolide with LmexGPDH (Figure 26) lies in a cavity surrounded by Arg 274, Phe 26, Lys 125, Phe 156, Val 298, Lys 210, and Ala 157. Lys 125 and Lys 210 have been identified as critical to catalytic activity of this enzyme [15]. With the exception of lanosterol, the steroid ligands showed preferential docking to LmajMetRS. The lowest-energy poses for these steroids show them all occupying the methionyl adenylate binding site (Figure 27). The tetracyclic steroidal structures all occupy the same position in a hydrophobic pocket surrounded by Asp 486, Trp 515, Lys 522, His 228, Gly 227, His 513, and Tyr 218, and hydrogen-bonded by way of the 3-hydroxyl group of the steroid to Trp 516 and Gly 514. Clerosterol has shown in vitro antileishmanial activity [68], while saringosterol, stigmasterol, and 24-hydroperoxy-24-vinylcholesterol, in addition to clerosterol, have shown in vitro antitrypanosomal activity [69]. β-Sitosterol has shown modest antitrypanosomal activity [70].
Table 29. MolDock docking energies (kJ/mol) of limonoids with Leishmania major protein targets.
Table 29. MolDock docking energies (kJ/mol) of limonoids with Leishmania major protein targets.
LimonoidsLmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLmajNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
11α−Acetoxy−2α−hydroxy−6−deoxyswietenine_acetate−77.4−100.5−112.6−84.0−112.9−113.7−79.4−90.7−99.9−85.3−106.7−103.7
3− O−Acetylanthothecanolide−102.6−129.9−114.6−91.2−111.4−121.1−103.5−96.4−102.1−103.7−106.8−107.6
3− O−Acetylkhayalactone−70.4−103.4−96.4−98.9−115.9−123.4−96.9−109.5−109.5−114.5−106.6−123.7
1− O−Acetylkhayanolide A−87.7−103.2−85.4−86.3−96.5−114.1−92.2−93.2−88.7−81.1−105.0−106.8
1− O−Acetylkhayanolide B−80.0−86.6−87.0−87.1−80.7−105.0−105.5−74.5−72.8−91.8−95.5−94.5
3− O−Acetylswietenine−79.2−90.6−95.8−69.9−102.9−104.3−82.6−84.6−82.4−92.3−95.5−121.8
3− O−Acetylswietenolide−91.9−115.0−92.7−82.9−98.6−115.0−74.1−81.5−86.8−80.1−93.6−100.2
6− O−Acetylswietenolide−87.9−107.6−80.0−86.6−97.4−102.0−81.6−98.4−85.7−96.3−107.5−108.7
Anthothecanolide−103.7−133.3−85.5−101.6−93.7−112.3−98.4−94.8−104.4−97.4−96.8−114.1
Carapa spirolactone−92.7−91.4−87.0−89.7−99.1−90.6−93.9−104.0−71.8−92.1−95.7−86.5
Carapin−79.9−109.2−89.9−95.0−92.8−95.0−84.8−92.6−86.4−88.3−98.9−110.5
Carapolide A−107.8−140.0−101.1−114.9−111.7−119.2−98.5−113.5−92.4−125.5−107.1−123.5
Carapolide B−104.9−128.3−88.1−117.3−111.7−117.4−124.7−106.0−82.3−98.6−107.9−107.4
Carapolide C−94.5−105.1−82.7−106.2−99.2−110.1−118.5−109.8−76.3−95.5−104.4−107.8
7−Deacetoxy−7−oxogedunin−51.6−95.8−82.2−90.1−86.0−93.6−100.1−100.2−91.2−79.0−91.3−86.5
1− O−Deacetyl−6−deoxykhayanolide E−104.2−81.4−75.8−79.7−96.9−94.3−88.0−72.9−85.6−96.6−94.1−102.8
7−Deacetylgedunin−84.7−86.9−78.5−84.8−85.2−87.5−96.9−99.7−89.9−83.2−91.5−90.3
1− O−Deacetyl−2α−hydroxykhayanolide E−96.4−105.3−77.1−74.1−91.7−101.1−93.7−81.9−85.9−97.6−109.8−108.7
Deacetylkhayanolide E−104.7−85.6−76.5−80.6−88.0−97.2−87.0−72.6−83.1−98.8−110.8−102.9
1−Deacetylkhivorin−60.5−92.7−96.1−78.3−96.3−107.5−58.1−84.0−81.8−97.0−98.5−97.7
3−Deacetylkhivorin−73.2−95.7−90.4−71.8−96.0−110.6−99.1−99.4−81.4−82.4−98.7−108.2
7−Deacetylkhivorin−77.8−94.0−99.2−85.0−88.2−96.3−93.5−79.1−87.1−83.7−89.9−95.6
6−Deoxyswietenolide−84.5−100.2−79.3−84.0−97.3−108.8−90.1−84.6−93.8−90.9−98.2−100.5
3,7−Dideacetylkhivorin−81.5−93.0−83.4−64.8−105.3−96.3−93.9−109.3−108.1−76.6−104.4−99.6
Evodulone−83.0−113.4−87.5−83.7−103.1−103.3−96.8−114.6−87.5−80.9−96.0−101.9
Fissinolide−89.4−112.8−93.5−80.4−99.0−121.6−99.6−85.5−94.3−110.6−88.8−97.1
Gedunin−74.5−106.8−81.4−70.2−89.5−102.1−93.5−102.8−96.4−87.1−93.1−97.7
Grandifolide A−75.5−113.8−93.3−101.7−115.1−128.4−96.9−94.9−95.7−98.4−108.3−102.9
Grandifolin−91.5−110.0−99.7−92.9−96.2−100.3−94.8−94.1−114.7−95.8−108.9−100.0
Grandifoliolenone−84.6−88.5−89.0−88.7−103.9−106.0−102.8−97.8−89.6−86.1−94.2−119.8
Grandifotane−102.5−154.5−94.6−80.1−99.5−106.1−90.4−107.9−96.4−96.5−104.0−112.7
6−Hydroxykhayalactone−112.4−105.3−89.5−111.0−106.7−116.6−92.8−88.3−98.9−101.2−111.5−126.4
3β−Isobutyryloxy−1−oxomeliac−8(30)−enate−95.6−119.9−109.6−89.9−101.4−111.4−105.5−81.3−98.8−86.9−109.1−110.0
Khayalactone−107.6−110.0−90.3−103.4−102.6−115.8−92.1−96.1−104.7−101.0−113.2−126.4
Khayanolide A−110.8−123.5−101.3−104.4−111.1−115.5−98.4−105.9−107.9−138.5−127.4−123.9
Khayanolide B−104.1−93.6−77.9−86.4−93.6−99.7−94.8−59.4−86.1−97.9−99.8−105.4
Khivorin−75.6−98.7−99.2−91.1−99.1−101.7−97.5−77.8−92.1−89.3−101.3−109.6
Methyl acetoxyangolensate−90.2−102.1−75.7−99.5−102.2−107.2−82.9−93.5−80.3−108.2−98.2−94.5
Methyl angolensate−89.2−104.2−82.9−100.1−92.6−109.9−85.1−90.8−79.7−110.5−113.2−108.6
Methyl hydroxyangolensate−82.9−91.4−73.0−102.8−87.6−109.2−73.0−84.1−79.5−100.2−108.8−101.4
Methyl ivorensate−79.5−106.7−95.7−102.4−98.9−99.8−84.7−76.1−87.2−95.8−106.5−108.2
Mexicanolide−86.9−103.0−82.7−79.6−95.4−111.6−90.8−90.2−95.6−100.5−93.9−103.4
Proceranolide−86.5−110.3−77.8−96.1−97.0−108.7−76.0−91.5−94.3−91.7−102.2−102.0
Proceranolide butanoate−94.0−119.7−87.9−93.8−97.5−119.2−95.9−103.9−89.2−90.9−107.1−106.6
Proceranone−84.4−103.0−93.9−97.8−101.8−106.0−88.2−115.6−91.4−82.7−89.5−113.2
Procerin−71.9−98.4−75.8−19.8−76.4−96.8−67.9−46.1−70.5−58.8−88.9−78.6
Seneganolide−101.7−122.0−94.5−106.6−96.4−110.3−92.6−92.4−104.9−106.9−105.8−104.6
Swiemahogin A−92.4−125.6−91.5−115.5−116.8−119.1−103.7−122.0−81.1−111.1−106.4−123.7
Swietenine−93.7−114.2−99.4−84.6−113.1−107.1−88.8−87.7−87.6−91.1−106.8−110.9
Swietenolide−85.7−108.1−80.4−83.7−97.4−109.0−71.8−82.8−84.3−102.3−97.4−98.9
1,3,7−Trideacetylkhivorin−86.0−95.7−79.2−76.7−94.8−88.5−101.1−97.0−61.9−81.2−97.1−84.1
Table 30. MolDock docking energies (kJ/mol) of limonoids with Leishmania donovani and L. mexicana protein targets.
Table 30. MolDock docking energies (kJ/mol) of limonoids with Leishmania donovani and L. mexicana protein targets.
LimonoidsLdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
Site 1Site 2Site 3
11α−Acetoxy−2α−hydroxy−6−deoxyswietenine acetate−92.2−85.4−46.3−82.9−94.0−99.6−88.0−121.3−95.5−103.8−103.9−81.9
3−O−Acetylanthothecanolide−100.8−85.9−54.7−70.9−108.1−100.9−94.3−117.9−110.2−97.0−94.7−97.5
3−O−Acetylkhayalactone−77.2−66.9−90.3−100.7−108.8−113.1−104.3−110.2−104.4−111.4−107.4−107.8
1−O−Acetylkhayanolide A−80.2−47.6−38.3−92.4−96.6−115.5−103.5−110.9−116.4−101.2−90.2−84.7
1−O−Acetylkhayanolide B−81.3−68.4−65.9−72.5−83.2−106.6−82.6−88.0−94.9−84.9−91.4−82.7
3−O−Acetylswietenine−75.2−78.2−57.4−106.0−74.8−118.6−81.1−106.8−101.8−108.3−103.5−61.4
3−O−Acetylswietenolide−88.0−81.2−37.9−106.8−72.1−103.8−83.5−89.0−98.3−95.5−96.0−68.2
6−O−Acetylswietenolide−86.6−69.6−58.4−91.1−82.4−142.7−92.8−85.9−110.1−97.9−95.8−67.7
Anthothecanolide−97.5−66.6−69.0−92.0−95.0−99.1−86.8−118.1−100.7−98.3−91.0−91.5
Carapa spirolactone−89.9−75.5−65.2−61.7−88.6−94.8−78.3−96.5−91.4−94.8−85.9−78.6
Carapin−71.7−102.8no dock−94.8−84.6−106.0−78.4−99.7−104.6−94.8−82.9−78.9
Carapolide A−113.0−101.2−88.5−97.5−88.6−118.9−94.1−112.6−114.2−115.6−106.5−100.6
Carapolide B−96.9−82.5−21.9−93.1−90.7−107.7−90.1−98.7−107.0−109.9−99.4−91.4
Carapolide C−102.9−99.2−58.0−78.9−83.1−112.1−88.5−115.3−107.4−113.3−98.4−94.4
7−Deacetoxy−7−oxogedunin−68.4−66.9−14.8−79.7−79.6−92.1−73.6−83.5−111.5−101.0−95.5−83.9
1−O−Deacetyl−6−deoxykhayanolide E−101.8−87.2−70.1−73.5−82.3−99.9−82.4−75.6−97.4−99.5−91.7−71.8
7−Deacetylgedunin−52.7−81.4−11.3−82.6−84.8−91.5−74.1−82.5−98.3−93.9−93.3−80.6
1−O−Deacetyl−2α−hydroxykhayanolide E−98.1−58.4−48.5−64.2−79.0−111.8−87.0−84.9−100.4−104.5−86.2−66.2
Deacetylkhayanolide E−96.2−69.1−56.0−58.8−84.2−92.6−85.0−77.8−97.5−101.8−88.6−64.2
1−Deacetylkhivorin−52.5−89.2no dock−74.9−76.6−99.4−83.8−84.7−98.4−106.4−93.5−66.4
3−Deacetylkhivorin−68.8−92.2−66.2−84.2−96.9−100.5−99.7−85.4−98.4−91.3−79.4−71.6
7−Deacetylkhivorin−68.1−68.6−36.1−94.8−88.0−99.8−83.1−85.5−105.3−104.6−94.1−75.9
6−Deoxyswietenolide−90.3−75.0no dock−94.3−74.2−114.6−84.8−105.7−90.4−86.9−94.5−73.0
3,7−Dideacetylkhivorin−62.6−69.3−63.2−87.3−92.3−96.2−88.0−78.6−113.5−85.2−98.5−73.1
Evodulone−80.2−84.8−74.3−90.6−79.0−98.7−86.6−103.2−103.4−105.3−93.2−88.4
Fissinolide−83.6−80.3−54.6−102.4−64.2−95.1−85.1−111.9−90.4−95.2−92.9−78.1
Gedunin−84.0−88.2no dock−88.3−85.0−98.3−80.4−82.0−88.4−99.1−95.6−88.9
Grandifolide A−77.1−96.3no dock−98.1−91.2−103.8−90.9−93.4−104.5−115.5−87.3−85.8
Grandifolin−53.7−94.9−67.0−73.2−83.7−109.1−89.4−95.4−105.1−98.9−104.0−99.3
Grandifoliolenone−93.7−93.8−68.9−77.3−78.7−115.1−80.0−101.4−115.4−103.6−100.1−87.3
Grandifotane−99.7−70.8−40.6−99.4−107.8−113.7−87.5−117.2−100.5−100.6−106.8−29.1
6−Hydroxykhayalactone−106.7−80.2−88.2−96.4−94.0−106.1−97.3−98.6−103.4−110.1−91.2−95.9
3β−Isobutyryloxy−1−oxomeliac−8(30)−enate−92.4−82.3no dock−99.8−87.6−99.2−87.8−89.7−95.3−117.6−92.1−60.0
Khayalactone−107.0−68.1−55.1−97.7−94.6−116.0−95.9−102.0−100.2−100.8−95.6−94.2
Khayanolide A−110.9−98.7−18.3−97.8−92.5−137.8−98.6−112.1−115.3−107.8−107.3−89.9
Khayanolide B−102.5−72.5−39.5−70.4−90.8−94.6−88.3−77.6−88.2−105.2−94.7−71.2
Khivorin−64.6−89.4−72.0−30.2−92.4−107.4−82.0−84.0−93.9−108.2−85.6−78.8
Methyl acetoxyangolensate−89.1−58.8−59.5−88.8−98.0−94.6−72.7−81.8−108.9−98.4−94.8−41.3
Methyl angolensate−89.5−52.0−74.5−27.42−98.6−112.9−75.3−109.7−99.1−95.9−87.2−79.6
Methyl hydroxyangolensate−91.0−73.9−74.7−75.6−94.5−115.7−76.6−112.5−93.1−93.7−87.6−78.9
Methyl ivorensate−86.9−75.4−63.9−82.2−102.0−119.7−77.1−80.8−104.0−91.3−96.2−70.8
Mexicanolide−85.4−67.6−33.9−84.3−67.9−112.8−92.2−105.5−97.3−90.4−98.3−59.4
Proceranolide−90.2−77.6no dock−94.7−66.8−121.6−87.2−106.0−90.0−88.8−94.6−73.9
Proceranolide butanoate−94.7−81.0−70.3−111.8−76.2−92.9−89.1−95.1−100.9−106.8−107.4−63.0
Proceranone−87.7−89.0no dock−84.6−75.0−99.3−86.0−109.9−98.0−108.4−87.7−98.6
Procerin−77.5−22.4−59.7−107.5−94.8−111.3−108.8−84.5−93.9−86.6−70.7−64.8
Seneganolide−99.5−92.0−51.9−88.4−89.9−98.8−86.6−109.8−95.9−92.5−92.5−83.5
Swiemahogin A−69.7−94.9−52.2−81.4−79.9−125.4−92.8−117.4−120.1−106.2−110.0−91.4
Swietenine−90.7−67.4no dock−99.3−85.0−104.1−86.3−91.6−99.6−122.3−100.7−78.0
Swietenolide−87.3−72.3no dock−93.6−72.3−121.0−88.9−94.4−99.2−91.2−87.7−68.3
1,3,7−Trideacetylkhivorin−53.7−80.5no dock−76.2−87.1−97.2−81.2−71.5−96.9−93.0−82.8−83.2
Table 31. MolDock docking energies (kJ/mol) of limonoids with Leishmania infantum protein targets.
Table 31. MolDock docking energies (kJ/mol) of limonoids with Leishmania infantum protein targets.
LimonoidsLinfCYP51LinfGLO2LinfPnC1LinfTDR1LinfTR
11α−Acetoxy−2α−hydroxy−6−deoxyswietenine acetate−98.0−75.1no dock−93.6−89.4
3−O−Acetylanthothecanolide−102.5−77.7no dock−82.5−101.6
3−O−Acetylkhayalactone−116.2−99.5no dock−103.7−113.2
1−O−Acetylkhayanolide A−102.4−89.1no dock−87.9−108.3
1−O−Acetylkhayanolide B−114.3−82.0no dock−80.6−84.0
3−O−Acetylswietenine−95.3−74.9no dock−76.4−84.2
3−O−Acetylswietenolide−105.4−80.3no dock−79.5−95.4
6−O−Acetylswietenolide−103.1−77.4no dock−91.1−92.6
Anthothecanolide−107.9−74.6−57.2−82.9−94.3
Carapa spirolactone−108.8−69.7no dock−68.3−87.3
Carapin−94.3−80.2no dock−80.9−86.3
Carapolide A−111.8−89.1no dock−98.1−98.3
Carapolide B−103.1−71.6no dock−91.8−92.9
Carapolide C−106.9−80.4no dock−79.4−92.5
7−Deacetoxy−7−oxogedunin−104.3−71.9no dock−70.0−84.6
1− O−Deacetyl−6−deoxykhayanolide E−98.0−77.3no dock−78.6−90.9
7−Deacetylgedunin−91.2−72.8no dock−72.6−80.4
1− O−Deacetyl−2α−hydroxykhayanolide E−110.6−75.1no dock−83.8−88.6
Deacetylkhayanolide E−103.4−81.0−45.4−83.0−84.9
1−Deacetylkhivorin−101.2−72.0no dock−75.8−87.7
3−Deacetylkhivorin−106.0−76.8no dock−76.0−98.3
7−Deacetylkhivorin−94.5−83.8no dock−87.0−73.7
6−Deoxyswietenolide−95.9−76.5no dock−83.0−92.4
3,7−Dideacetylkhivorin−95.9−74.8no dock−76.3−103.3
Evodulone−105.3−81.6no dock−88.6−87.5
Fissinolide−99.2−78.0no dock−78.8−99.0
Gedunin−107.4−75.9no dock−82.2−78.4
Grandifolide A−109.3−89.6no dock−90.2−99.8
Grandifolin−105.8−76.1no dock−75.8−96.8
Grandifoliolenone−98.7−90.7−43.1−75.9−92.7
Grandifotane−111.5−80.8no dock−89.8−90.0
6−Hydroxykhayalactone−116.0−83.1no dock−100.2−98.6
3β−Isobutyryloxy−1−oxomeliac−8(30)−enate−102.7−78.4no dock−82.5−103.4
Khayalactone−101.0−90.6no dock−100.3−97.5
Khayanolide A−104.5−83.4no dock−84.3−97.4
Khayanolide B−110.0−77.4−44.1−97.2−103.1
Khivorin−100.9−71.4no dock−82.0−93.8
Methyl acetoxyangolensate−99.6−66.4no dock−84.9−82.8
Methyl angolensate−90.5−71.0no dock−77.8−85.6
Methyl hydroxyangolensate−95.8−65.2−48.5−78.2−85.4
Methyl ivorensate−95.5−77.8no dock−85.2−92.5
Mexicanolide−90.4−78.8−27.5−75.8−92.3
Proceranolide−95.7−78.9no dock−83.1−91.5
Proceranolide butanoate−100.6−82.1no dock−89.5−93.5
Proceranone−107.9−89.7no dock−90.7−94.6
Procerin−94.9−70.1no dock−68.8−81.8
Seneganolide−101.8−76.9no dock−82.0−86.4
Swiemahogin A−113.3−84.7no dock−93.4−97.4
Swietenine−108.3−79.6no dock−83.2−87.1
Swietenolide−97.0−72.7no dock−86.3−93.3
1,3,7−Trideacetylkhivorin−92.0−73.6no dock−62.4−86.6
Table 32. MolDock docking energies (kJ/mol) of withanolides with Leishmania major protein targets.
Table 32. MolDock docking energies (kJ/mol) of withanolides with Leishmania major protein targets.
WithanolidesLmajCatBLmajDHODHLmajdUTPaseLmajNDKbLmajNHLmajNMTLmajOPBLmajPDE1LmajPTR1LmajMetRSLmajTyrRSLmajUGPase
24,25−Epoxywithanolide D−92.9−121.0−109.3−104.7−104.2−124.1−102.7−114.1−114.2−98.2−119.5−108.2
14−Hydroxyixocarpanolide−77.9−104.9−89.2−77.9−100.9−98.2−90.0−113.0−81.8−99.0−99.6−106.6
Physagulin A−102.7−123.7−98.3−103.1−108.2−113.7−100.6−115.8−110.0−98.4−104.0−110.6
Physagulin B−97.0−107.6−89.8−105.1−104.5−119.6−95.6−103.5−93.8−114.8−106.0−111.0
Physagulin C−93.4−99.5−89.6−105.5−106.5−113.8−95.9−118.3−93.8−127.3−105.0−122.7
Physagulin F−92.8−88.2−88.0−96.5−106.1−102.6−96.9−107.5−90.9−133.2−98.8−98.5
Physagulin H−91.8−112.0−88.3−92.9−105.4−111.2−103.2−111.8−95.5−126.1−104.1−112.8
Physagulin I−94.2−107.1−92.3−99.1−107.6−103.0−97.3−110.6−92.1−123.8−103.8−106.2
Physagulin J−96.8−105.4−87.2−90.6−96.5−106.7−94.5−117.6−91.2−105.6−100.1−110.1
Physagulin K−97.5−118.5−81.7−69.4−111.2−112.6−108.9−108.9−95.5−101.7−97.3−104.1
Physagulin L−98.8−114.8−88.0−69.9−111.2−112.1−110.3−97.3−106.0−103.0−99.2−107.6
Physagulin L'−107.0−109.0−104.2−99.2−99.7−114.2−108.2−111.9−108.2−115.0−103.5−101.3
Physagulin M−72.5−95.0−90.9−83.2−104.8−110.0−88.3−95.8−89.1−92.9−103.3−115.4
Physagulin M'−88.5−115.0−93.6−99.3−98.2−112.8−92.4−106.9−97.1−120.2−100.5−101.0
Physagulin N−93.1−102.8−92.3−93.1−101.9−115.2−94.7−108.5−84.4−110.6−106.6−118.1
Physagulin N'−94.4−102.5−72.7−94.6−99.7−99.0−96.1−116.1−90.0−110.4−90.2−91.9
Physagulin O−87.3−94.3−81.5−91.4−100.8−103.6−95.0−98.0−87.0−88.9−95.5−108.1
Physalin A−86.5−92.6−71.2−86.8−87.3−92.0−110.7−70.2−75.0−84.2−90.0−101.2
Physalin B−76.9−92.3−80.8−62.9−90.0−100.2−86.9−95.8−76.7−78.1−88.3−101.7
Physalin D−83.9−87.6−85.1−65.4−101.7−99.7−86.9−85.4−68.4−83.2−83.8−96.5
Physalin E−82.1−91.5−85.3−65.5−88.5−100.6−94.1−76.3−66.7−83.2−82.2−99.1
Physalin F−81.2−90.1−80.7−66.0−93.0−101.4−83.5−96.3−73.2−78.0−96.7−101.7
Physalin G−95.6−103.9−80.1−82.3−96.3−89.6−91.7−91.6−88.0−89.8−103.5−103.8
Physalin H−82.8−89.5−80.4−65.0−98.4−95.8−86.2−86.6−67.2−80.8−87.1−93.0
Physalin I−78.8−85.4−82.6−71.4−85.9−93.0−87.3−75.2−60.5−79.5−82.5−98.4
Physalin J−80.2−91.0−85.1−74.9−96.4−103.1−86.6−91.8−73.9−77.7−84.1−94.1
Physalin K−83.1−106.9−73.7−81.7−87.5−88.7−66.7−68.5−71.5−77.6−81.3−105.3
Physalin U−81.2−96.3−83.0−50.7−93.4−93.0−90.4−99.2−74.5−85.2−91.9−103.1
Physalin V−88.4−101.1−83.0−83.5−103.5−100.9−96.4−95.5−79.4−84.8−86.9−107.5
Physalin W−93.4−95.0−85.1−75.9−91.0−92.0−78.6−100.4−80.2−84.0−91.7−110.3
Physangulide−101.9−88.9−104.0−97.8−101.8−109.1−92.9−117.4−110.6−104.4−96.4−101.8
Physanolide A−85.7−102.9−84.6−69.0−97.6−107.9−93.8−103.5−100.5−94.5−88.4−101.1
Vamonolide−83.4−96.7−87.8−109.9−95.7−103.8−96.5−109.0−84.4−92.2−106.7−97.4
Withangulatin A−92.4−121.9−97.8−108.1−110.6−124.2−97.1−112.9−110.1−99.4−105.1−112.2
Withangulatin B−105.4−89.8−96.1−96.6−95.7−99.9−94.3−107.2−96.2−117.9−104.7−91.0
Withangulatin C−85.7−93.6−86.6−100.7−90.1−109.7−106.3−89.2−94.1−125.9−104.6−98.5
Withangulatin D−88.8−80.3−89.4−102.6−96.6−107.2−92.0−113.3−86.9−126.2−105.2−104.8
Withangulatin E−57.3−94.8−36.3−92.5−85.7−102.4−89.1−95.7−88.9−96.0−112.7−97.9
Withangulatin F−85.1−96.0−83.8−103.9−97.7−98.9−87.9−120.8−85.8−96.0−102.4−96.9
Withangulatin G−91.5−122.3−76.0−100.4−95.2−100.1−93.7−99.7−87.6−97.7−105.8−92.5
Withangulatin H−91.6−105.5−89.1−96.8−81.0−94.8−105.1−88.8−71.0−115.3−102.2−106.9
Withangulatin I−98.8−112.4−90.0−91.3−106.6−113.1−88.1−105.6−106.0−98.2−102.3−110.7
Table 33. MolDock docking energies (kJ/mol) of withanolides with Leishmania donovani and L. mexicana protein targets.
Table 33. MolDock docking energies (kJ/mol) of withanolides with Leishmania donovani and L. mexicana protein targets.
LdonCatBLdonCypLdonDHODHLdonNMTLmexGAPDHLmexGPDHLmexPGILmexPMMLmexPYKLmexPYKLmexPYKLmexTIM
WithanolidesSite 1Site 2Site 3
24,25−Epoxywithanolide D−95.7−101.5−63.4−103.0−97.7−118.1−110.4−125.7−119.7−106.2−113.6−95.4
14−Hydroxyixocarpanolide−88.0−92.8−30.7−52.2−80.7−102.3−77.5−95.6−103.6−92.2−100.3−74.3
Physagulin A−97.4−103.3−82.8−91.9−91.4−116.2−100.5−119.2−111.6−104.4−106.5−85.0
Physagulin B−105.4−104.2−85.9−89.9−94.2−107.6−96.3−114.4−110.3−109.3−103.8−82.9
Physagulin C−98.7−86.0−80.6−104.7−91.6−108.7−98.2−124.7−103.4−100.7−103.8−85.9
Physagulin F−94.8−88.7−84.6−93.6−88.7−106.0−87.9−107.8−105.8−106.3−91.6−82.3
Physagulin H−96.5−85.2−83.6−98.8−86.0−101.4−97.2−113.0−106.2−104.6−101.7−79.3
Physagulin I−95.9−87.5−77.2−94.7−90.2−99.9−91.5−102.3−101.2−103.5−95.0−77.7
Physagulin J−94.4−84.6−60.7−92.5−88.5−108.7−91.2−100.6−98.5−111.2−100.6−86.6
Physagulin K−85.1−95.8no dock−92.5−94.2−109.1−90.1−92.6−112.2−106.4−97.1−76.0
Physagulin L−90.6−83.3−67.6−97.6−96.2−112.3−98.2−104.5−117.3−103.6−92.0−68.1
Physagulin L'−108.8−104.3−102.2−94.7−94.2−110.7−87.0−109.4−111.5−98.2−105.4−101.2
Physagulin M−91.2−91.3−70.6−81.4−96.1−101.8−78.6−87.4−105.6−111.5−101.9−75.9
Physagulin M'−84.3−94.8−30.7−90.9−89.8−106.2−88.9−88.5−110.5−103.7−96.3−106.7
Physagulin N−94.9−99.8−89.5−95.8−95.0−106.2−80.7−115.1−105.1−112.2−95.4−82.5
Physagulin N'−93.2−83.6−65.4−85.2−86.2−112.3−83.4−103.2−107.5−103.8−85.1−55.3
Physagulin O−90.3−88.8−88.3−93.9−93.4−103.5−84.5−94.6−99.4−102.4−106.3−72.0
Physalin A−85.6−71.4−41.9−82.3−83.6−93.8−82.0−102.9−88.1−100.4−91.4−81.7
Physalin B−84.9−71.7−48.5−81.8−78.4−88.5−84.8−92.6−92.0−89.4−84.8−73.9
Physalin D−82.6−79.1−54.4−80.5−79.6−91.8−84.5−85.0−89.8−95.0−79.9−71.7
Physalin E−83.4−63.3−30.0−75.9−81.3−83.5−74.5−83.7−96.2−93.5−81.5−76.0
Physalin F−83.7−73.8−57.4−83.2−80.7−92.8−92.4−85.1−90.9−91.0−76.6−74.9
Physalin G−93.6−71.0−81.2−92.5−76.9−78.4−87.9−97.9−100.6−90.4−93.0−69.2
Physalin H−85.2−60.7no dock−73.0−81.0−92.5−86.0−81.7−92.6−89.6−81.2−70.1
Physalin I−84.2−51.6no dock−68.3−82.5−96.2−87.4−79.0−84.0−86.5−82.9−61.6
Physalin J−83.1−80.1−55.5−79.5−82.2−92.4−78.2−97.8−97.0−94.9−88.0−72.1
Physalin K−82.6−74.7−65.5−84.2−70.4−90.2−77.6−76.5−96.7−87.4−94.2−60.7
Physalin U−83.0−65.1−68.5−94.0−85.9−97.6−93.2−85.0−97.0−93.2−85.9−81.6
Physalin V−83.2−83.6−27.1−84.3−81.2−93.9−93.1−82.8−95.0−92.7−90.5−52.8
Physalin W−93.9−67.5−77.2−89.7−84.0−101.5−92.1−91.4−98.1−99.0−86.9−80.2
Physangulide−103.2−99.4−71.3−106.0−89.9−105.2−83.7−111.5−114.6−108.0−103.3−82.8
Physanolide A−93.4−96.3−22.9−103.0−84.0−99.6−81.4−106.3−97.4−96.3−86.2−44.5
Vamonolide−83.4−89.7−52.6−90.2−75.4−96.2−81.5−107.1−101.6−100.9−90.8−77.4
Withangulatin A−106.1−102.6−39.9−98.6−96.7−119.8−105.4−122.0−109.2−102.9−107.5−87.8
Withangulatin B−95.7−90.0no dock−94.6−87.5−99.4−85.5−94.2−99.6−106.1−112.4−92.4
Withangulatin C−91.7−87.1−27.3−90.6−88.3−110.5−87.0−99.0−106.2−101.2−113.8−78.8
Withangulatin D−101.2−92.4no dock−93.6−84.6−105.1−86.5−96.2−92.3−104.8−108.2−86.5
Withangulatin E−81.0−77.9−25.9−95.5−76.9−105.7−85.8−99.9−102.7−101.4−100.8−87.8
Withangulatin F−54.3−94.3−58.6−83.3−88.7−108.4−88.3−100.2−106.2−97.7−104.7−99.5
Withangulatin G−91.5−87.6no dock−96.1−74.2−100.9−85.5−100.5−99.8−103.2−95.7−64.3
Withangulatin H−95.2−85.5−65.1−85.9−80.3−102.5−75.5−98.8−95.8−106.9−97.6−80.7
Withangulatin I−93.5−95.3−82.6−93.6−95.5−113.7−89.3−114.2−116.1−105.4−94.5−71.1
Table 34. MolDock docking energies (kJ/mol) of withanolides with Leishmania infantum protein targets.
Table 34. MolDock docking energies (kJ/mol) of withanolides with Leishmania infantum protein targets.
WithanolidesLinfCYP51LinfGLO2LinfPnC1LinfTDR1LinfTR
24,25−Epoxywithanolide D−128.1−102.8no dock−103.8−98.4
14−Hydroxyixocarpanolide−111.7−81.1no dock−85.3−94.4
Physagulin A−106.7−88.5no dock−103.6−102.7
Physagulin B−107.7−82.8no dock−99.0−95.1
Physagulin C−122.5−98.8no dock−99.7−94.2
Physagulin F−108.2−70.6no dock−80.8−96.1
Physagulin H−114.9−92.6no dock−96.8−91.9
Physagulin I−102.9−75.1no dock−84.5−97.7
Physagulin J−115.4−79.4no dock−87.5−93.2
Physagulin K−105.4−76.4no dock−88.5−95.0
Physagulin L−109.4−83.5no dock−90.1−94.7
Physagulin L '−107.4−90.3no dock−102.4−101.4
Physagulin M−106.5−78.5no dock−95.7−94.4
Physagulin M '−113.3−81.6no dock