Identification of Potential Leishmania N-Myristoyltransferase Inhibitors from Withania somnifera (L.) Dunal: A Molecular Docking and Molecular Dynamics Investigation
Abstract
:1. Introduction
1.1. Overview of the Antileishmanial Properties of Withania somnifera
1.2. Immunomodulatory Effects of W. somnifera in Leishmaniasis Infections
1.3. Molecular Docking Studies in the Development of Antileishmanial Drugs
2. Experimental
2.1. Phytochemical Review and Data Collection
2.2. Molecular-Docking Simulation
2.3. Molecular-Dynamics Simulation
3. Results
4. Discussion
Molecular-Dynamics Simulation Study
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug | Mode of Action | |
---|---|---|
Sodium stibogluconate | Meglumine antimoniate | Inhibit the parasite’s glycolysis and fatty acids β-oxidation |
Amphotericin B | Binds the membrane sterols of the parasite and alters its permeability to K+ and Mg2+ selectively | |
Pentamidine | Interferes with DNA synthesis and modifies the morphology of the kinetoplast | |
Miltefosine | Associated with leishmanial alkyl-lipid metabolism and phospholipid biosynthesis | |
Paromomycin | Inhibits the protein biosynthesis in sensitive Leishmania parasites |
No. | Name | Pose Score (kcal/mol) | Reference for Compound Isolation |
---|---|---|---|
Alkaloids | |||
1 | Somniferine | −16.4 | [43] |
2 | D-α-Aminoadipic acid | −13.8 | [44] |
3 | Anaferine | −12.6 | [45] |
4 | Anahygrine | −11.2 | [45] |
5 | Tropine | −11.2 | [46] |
6 | Cuscohygrine | −10.7 | [45] |
7 | Isopelletierine | −10.4 | [47] |
8 | Putrescine | −10.0 | [48] |
9 | γ-Aminobutyric acid | −9.6 | [44] |
10 | Withasomnine | −9.0 | [49] |
Phenolic compounds | |||
1 | Calycopteretin-3-rutinoside * | −23.3 | [50] |
2 | N-trans-feruloyl-methoxytyramine | −16.9 | [51] |
3 | Naringenin | −15.8 | [44] |
4 | Quercetin | −15.7 | [44] |
5 | Kaempferol | −15.4 | [44] |
6 | Catechin | −14.4 | [44] |
7 | Withaninsam A | −13.5 | [52] |
8 | Butein | −13.1 | [53] |
9 | Withaninsam B | −12.6 | [52] |
10 | Vanillic acid | −12.4 | [54] |
11 | Syringic acid | −12.2 | [55] |
12 | Acetosyringone | −12.0 | [56] |
13 | Aesculetin | −11.7 | [57] |
14 | Podocarpic acid | −10.3 | [44] |
15 | P-Coumaric acid | −9.1 | [58] |
Sterols | |||
1 | 3β-Stigmasta-5,24-dien-3-ol | −13.6 | [59] |
2 | Campesterol | −13.6 | [44] |
3 | Stigmasterol acetate | −13.5 | [60] |
4 | β-Sitosterol oleate | −13.3 | [60] |
5 | β-Sitosterol | −11.7 | [61] |
6 | Cholesterol | −11.6 | [44] |
7 | Stigmasterol | −11.3 | [61] |
8 | Brassicasterol | −11.1 | [44] |
9 | Crinosterol | −11.0 | [60] |
10 | 3β-Ergosta-5,24-dien-3-ol | −10.5 | [59] |
Withanones | |||
1 | Isowithanone | −15.6 | [62] |
2 | 27-Hydroxywithanone | −15.1 | [63] |
3 | 4α-Hydroxywithanone | −15.1 | [57] |
4 | 2,3-Dihydro-3β-hydroxywithanone | −15.0 | [64] |
5 | Withanone | −14.1 | [65] |
6 | 14β-Hydroxywithanone | −13.8 | [66] |
Chloride containing withanolides | |||
1 | Withanolide C | −15.7 | [67] |
2 | 4-Deoxyphysalolactone | −14.1 | [67] |
3 | (4β,5β,6α,22R) 5-Chloro-4,6,27-trihydroxy-1-oxowitha-2,24-dienolide 27-Acetate | −12.1 | [68] |
4 | Withanolide D chlorohydrin | −12.1 | [69] |
5 | 6α-Chloro-5β,17α-dihydroxywithaferin A | −11.8 | [70] |
6 | Withanolide Z | −11.7 | [28] |
Sulfur-containing withanolides | |||
1 | Withanolide sulfoxide | −17.7 | [71] |
2 | 5α,17α-Dihydroxy-6α,7α-epoxy-1-oxo-3β-O-sulfate-witha-24-enolide | −15.4 | [72] |
3 | 2,3-Dihydrowithanone-3β-O-sulfate | −14.6 | [73] |
4 | 2,3-Dihydrowithaferin A-3β-O-sulfate | −14.2 | [73] |
5 | Ashwagandhanolide | −14.2 | [74] |
Withanamides | |||
1 | Withanamide F * | −18.4 | [75] |
2 | Withanamide H | −17.3 | [75] |
3 | Withanamide E | −16.5 | [75] |
4 | Withanamide C | −15.7 | [75] |
5 | Withanamide G | −15.5 | [75] |
6 | Withanamide B | −15.4 | [75] |
7 | Withanamide A | −15.3 | [75] |
8 | Withanamide D | −15.0 | [75] |
9 | Withanamide I | −14.2 | [75] |
Withanolides | |||
1 | Withanolide A * | −18.7 | [66] |
2 | (4β,5β,6β,17α,22R) 5,6-Epoxy-4,17,27-trihydroxy-1-oxowitha-2,24-dienolide * | −18.5 | [66] |
3 | Somniferanolide | −18.0 | [76] |
4 | Withanolide H | −17.7 | [77] |
5 | 17-Isowithanolide E | −17.6 | [78] |
6 | Withanolide K | −17.4 | [79] |
7 | (20R,22R)14,20-Dihydroxy-1-oxowitha-2,4,6,24-tetraenolide | −17.4 | [66] |
8 | Withacoagulin I | −17.3 | [44] |
9 | 3α-(Uracil-1-yl)-2,3-dihydrowithaferin A | −17.1 | [80] |
10 | 14,17-Dihydroxywithanolide R | −17.0 | [57] |
11 | 27-Hydroxywithanolide D | −16.6 | [81] |
12 | Withanolide D | −16.6 | [82] |
13 | 24,25-Dihydro-27-desoxywithaferin A | −16.4 | [83] |
14 | Somniwithanolide | −16.3 | [76] |
15 | Withanolide S | −16.1 | [82] |
16 | 5,6:14,15-Diepoxy-4,27-dihydroxy-1-oxowitha-2,24-dienolide | −16.0 | [68] |
17 | (3α,4β,5β,6α,22R) 3,6-Epoxy-4,5,27-trihydroxy-1-oxowith-24-enolide | −15.9 | [84] |
18 | 3β-(Uracil-1-yl)-2,3-dihydrowithaferin A | −15.7 | [80] |
19 | Tubocapsanolide F | −15.6 | [85] |
20 | 4-Hydroxywithanolide E | −15.6 | [86] |
21 | Withanolide E | −15.4 | [79] |
22 | (3β,5α,6α,7α,17α,22R) 6,7-Epoxy-3,5,17-trihydroxy-1-oxowith-24-enolide | −15.4 | [72] |
23 | Quresimine B | −15.3 | [87] |
24 | Sominolide | −15.3 | [88] |
25 | Withanolide Ws 1 | −15.3 | [89] |
26 | Withanolide L | −15.2 | [79] |
27 | Withasomniferol C | −15.2 | [90] |
28 | Withacoagin | −15.2 | [91] |
29 | Somniferawithanolide | −15. 2 | [76] |
30 | 6,7-Epoxy-5,23-dihydroxy-1-oxowitha-2,24-Dienolide | −15.0 | [92] |
31 | Withaoxylactone | −14.8 | [93] |
32 | Dihydrowithaferin A | −14.8 | [63] |
33 | Withanolide J | −14.7 | [79] |
34 | 5-Deoxywithanolide R | −14.7 | [94] |
35 | Withanolide I | −14.7 | [79] |
36 | 17α-Hydroxywithanolide D | −14.5 | [81] |
37 | Withasomnilide | −14.4 | [76] |
38 | (3β,5α,6α,7α,20R,22R) 6,7-Epoxy-3,5,20-trihydroxy-1-oxowith-24-enolide | −14.4 | [95] |
39 | Withanolide G | −14.3 | [79] |
40 | 3β-O-Butyl-2,3-dihydrowithaferin A | −14. 3 | [80] |
41 | 27-Deoxywithaferin A | −14.3 | [96] |
42 | Pubesenolide (sominone) | −14.3 | [97] |
43 | Quresimine A | −14.2 | [93] |
44 | 27-Hydroxywithanolide B | −14.2 | [28] |
45 | Withanolide B | −14.2 | [98] |
46 | Withasomniferanolide | −14.1 | [76] |
47 | Somnifericin | −14.1 | [99] |
48 | 20-Deoxywithanolide D | −14.1 | [100] |
49 | (5α,6α,7α,16β,17(20)E) 6,7-Epoxy-5,16-dihydroxy-1-oxowitha-2,17(20),24-trienolide 16-acetate | −14.1 | [98] |
50 | Withanolide M | −14.0 | [79] |
51 | Withanolide O | −14.0 | [101] |
52 | Dunawithagenin | −13.9 | [102] |
53 | 5,6-Epoxy-4-hydroxy-1-oxowitha-2,16,24-trienolide | −13.9 | [72] |
54 | Withanolide U | −13.9 | [101] |
55 | (5α,17αOH,22R) 5,17-Dihydroxy-1-oxowitha-2,6,24-trienolide | −13.7 | [103] |
56 | 4-Deoxywithaperuvin | −13.7 | [104] |
57 | 5,6-Epoxy-20-hydroxy-1,4-dioxowitha-2,24-dienolide | −13.7 | [105] |
58 | 17-Hydroxywithaferin A | −13.6 | [106] |
59 | 2,3-Dehydrosomnifericin | −13.5 | [107] |
60 | 5,6-Epoxy-4-hydroxy-1-oxowitha-2,14,24-trienolide | −13.5 | [108] |
61 | Withanolide Q | −13.5 | [92] |
62 | Withasomniferin A | −13.5 | [94] |
63 | (14α,20R,22R)14,20-Dihydroxy-1-oxowitha-2,5,16,24-tetraenolide | −13.5 | [109] |
64 | 3β-(Adenin-9-yl)-2,3-dihydrowithaferin A | −13.4 | [80] |
65 | Withanolide F | −13.4 | [79] |
66 | Withanolide T | −13.3 | [66] |
67 | Withanolide Y | −13.3 | [110] |
68 | Withanolide N | −13.3 | [82] |
69 | Withacoagulin G | −13.2 | [44] |
70 | (4β,5β,6β,20R,22R) 5,6-Epoxy-4,20-dihydroxy-1-oxowith-24-enolide | −13.2 | [105] |
71 | 14α-Hydroxywithanolide D | −13.2 | [111] |
72 | 4-Dimethyloxocyclopropyl-2,3-dihydrowithaferin A | −13.1 | [83] |
73 | 24,25-Dihydrowithanolide D | −13.1 | [71] |
74 | Withanolide P | −12.8 | [81] |
75 | 5,6-Epoxy-20-hydroxy-1,4-dioxowith-2-Enolide | −12.6 | [112] |
76 | Withasomniferol B | −12.5 | [113] |
77 | Withaferin A | −12.5 | [114] |
78 | Withasomniferol A | −12.5 | [113] |
79 | 5,6-Epoxy-4,20-Dihydroxy-3-methoxy-1-oxowithanolide | −12.2 | [115] |
80 | 27-Deoxy-14-hydroxywithaferin A | −12.2 | [116] |
81 | Withanolide R | −11.9 | [92] |
82 | 27-Hydroxywithanolide I | −11.7 | [102] |
83 | Viscosalactone B | −11.6 | [117] |
84 | 5-Ethoxy-6,14,17,20-tetrahydroxy-1-oxowitha-2,24-dienolide | −11.6 | [102] |
85 | Withalactone | −11.5 | [93] |
86 | (1α,3β,5α,6α,7α,20S,22R) 6,7-Epoxy-1,3,5-trihydroxywith-24-enolide | −11.3 | [118] |
87 | Withasomidienone | −10.1 | [119] |
Withanosides | |||
1 | 4,16-Dihydroxy-5β,6β-epoxyphysagulin D * | −24.0 | [83] |
2 | Withanoside IX * | −22.2 | [84] |
3 | Physagulin D (1→6)-β-D-glucopyranosyl-(1→4)-β-D-glucopyranoside * | −22.1 | [83] |
4 | Withanoside VIII | −20.5 | [84] |
5 | Withanoside X * | −19.9 | [84] |
6 | Withanoside II * | −19.6 | [120] |
7 | Withanoside IV | −19.2 | [120] |
8 | 24,25-Dihydrowithanoside VI * | −18.5 | [75] |
9 | Sitoindoside IX * | −18.1 | [121] |
10 | Withanoside III | −17.8 | [120] |
11 | Withanoside VII | −17.5 | [120] |
12 | Withanoside V | −16.6 | [120] |
13 | Withanoside VI | −16.3 | [120] |
14 | Glucosomniferanolide | −16.1 | [90] |
15 | Withanoside XI | −15.7 | [84] |
16 | Sitoindoside VII | −14.4 | [122] |
17 | Sitoindoside VIII | −14.0 | [122] |
18 | Withanoside I | −14.0 | [120] |
19 | Sitoindoside X | −12.9 | [121] |
Energy Component | Calycopteretin 3-Rutinoside | Withanoside IX | 4,16-Dihydroxy-5,6- epoxyphysagulin D | Co-Crystalized Inhibitor |
---|---|---|---|---|
ΔGgas | −17.98 | −24.63 | −21.45 | −28.73 |
ΔGsolv | 9.76 | 16.15 | 11.64 | 15.44 |
ΔGTotal | −8.21 | −8.47 | −9.80 | −13.29 |
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Orabi, M.A.A.; Alshahrani, M.M.; Sayed, A.M.; Abouelela, M.E.; Shaaban, K.A.; Abdel-Sattar, E.-S. Identification of Potential Leishmania N-Myristoyltransferase Inhibitors from Withania somnifera (L.) Dunal: A Molecular Docking and Molecular Dynamics Investigation. Metabolites 2023, 13, 93. https://doi.org/10.3390/metabo13010093
Orabi MAA, Alshahrani MM, Sayed AM, Abouelela ME, Shaaban KA, Abdel-Sattar E-S. Identification of Potential Leishmania N-Myristoyltransferase Inhibitors from Withania somnifera (L.) Dunal: A Molecular Docking and Molecular Dynamics Investigation. Metabolites. 2023; 13(1):93. https://doi.org/10.3390/metabo13010093
Chicago/Turabian StyleOrabi, Mohamed A. A., Mohammed Merae Alshahrani, Ahmed M. Sayed, Mohamed E. Abouelela, Khaled A. Shaaban, and El-Shaymaa Abdel-Sattar. 2023. "Identification of Potential Leishmania N-Myristoyltransferase Inhibitors from Withania somnifera (L.) Dunal: A Molecular Docking and Molecular Dynamics Investigation" Metabolites 13, no. 1: 93. https://doi.org/10.3390/metabo13010093