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Structure-Based Design of Biologically Active Compounds

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 59513

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Prof. Dr. Sandra Gemma

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Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Interests: medicinal chemistry; small molecules; drug discovery; structure-activity relationships; anti-infective agents; parasitic diseases; chemotherapeutics; synthesis of biologically active compounds
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Dear Colleagues,

This Special Issue is entitled “Structure-based design of biologically active compounds”. The identification of new drugs is a challenging process characterized by a high attrition rate. In this context, structure-based design has long been used as an important and irreplaceable strategy in all the different steps of the drug discovery process such as hit identification, hit-to-lead progression, optimization of selectivity, off-target affinity, and drug-like properties. In recent years, significant advances in molecular biology, production of high quality proteins, and X-ray crystallography techniques (e.g. cryo bio-crystallography) has allowed a tremendous increase in our detailed structural knowledge of biologically-relevant target proteins. The rapid pace of development of new tools to better understand the structure and function of proteins, disease complexity, and pathophysiological correlations continues to fuel new potential targets for the development of innovative drugs. Structure-based design has the potential of addressing the challenges of modern medicinal chemistry in newly developing fields. Recent advances in network and systems biology has allowed the study of drug targets in their physiological context, fostering drug discovery approaches able to tackle the complexity of multifactorial diseases through the design of multitargeting ligands. The design of small molecules able to target protein–protein interactions is another challenging goal for which the contribution of structure-based design will be essential. As a last example, high-resolution structural knowledge of GPCR receptors has opened exciting new opportunities for the design of bitopic, divalent or biased ligands. This Special Issue will cover all the different aspects of structure-based design, leading to biologically active compounds, from hit/lead generation based on the structural knowledge of the target (X-ray or homology modeling), to molecular docking, synthetic chemistry, and structure–activity relationships for ligand optimization.

Prof. Dr. Sandra Gemma
Guest Editor

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Keywords

Structure-based design
Hit-to-lead transition
Molecular modeling
Small molecules
Enzyme inhibitors
Multitargeting ligands
Protein–protein interaction inhibitors
Structure–activity relationships

Published Papers (13 papers)

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Editorial

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2 pages, 147 KiB

Open AccessEditorial

Structure-Based Design of Biologically Active Compounds

by Sandra Gemma

Molecules 2020, 25(14), 3115; https://doi.org/10.3390/molecules25143115 - 8 Jul 2020

Cited by 2 | Viewed by 1378

Abstract

The past decades have witnessed tremendous progress in the detailed structural knowledge of proteins as potential or validated drug targets and the discovery of new drugs based on this wealth of knowledge progressed in parallel [...] Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

Research

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19 pages, 2808 KiB

Open AccessArticle

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors

by Tarfah Al-Warhi, Ahmed M. El Kerdawy, Nada Aljaeed, Omnia E. Ismael, Rezk R. Ayyad, Wagdy M. Eldehna, Hatem A. Abdel-Aziz and Ghada H. Al-Ansary

Molecules 2020, 25(9), 2031; https://doi.org/10.3390/molecules25092031 - 27 Apr 2020

Cited by 35 | Viewed by 3575

Abstract

On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC₅₀: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC₅₀: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC₅₀s equal 1.82 and 1.26 µM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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16 pages, 4139 KiB

Open AccessArticle

In Silico Screening for Novel Leucine Aminopeptidase Inhibitors with 3,4-Dihydroisoquinoline Scaffold

by Joanna Ziemska, Jolanta Solecka and Małgorzata Jarończyk

Molecules 2020, 25(7), 1753; https://doi.org/10.3390/molecules25071753 - 10 Apr 2020

Cited by 7 | Viewed by 4077

Abstract

Cancers are the leading cause of deaths worldwide. In 2018, an estimated 18.1 million new cancer cases and 9.6 million cancer-related deaths occurred globally. Several previous studies have shown that the enzyme, leucine aminopeptidase is involved in pathological conditions such as cancer. On the basis of the knowledge that isoquinoline alkaloids have antiproliferative activity and inhibitory activity towards leucine aminopeptidase, the present study was conducted a study which involved database search, virtual screening, and design of new potential leucine aminopeptidase inhibitors with a scaffold based on 3,4-dihydroisoquinoline. These compounds were then filtered through Lipinski’s “rule of five,” and 25 081 of them were then subjected to molecular docking. Next, three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed for the selected group of compounds with the best binding score results. The developed model, calculated by leave-one-out method, showed acceptable predictive and descriptive capability as represented by standard statistical parameters r² (0.997) and q² (0.717). Further, 35 compounds were identified to have an excellent predictive reliability. Finally, nine selected compounds were evaluated for drug-likeness and different pharmacokinetics parameters such as absorption, distribution, metabolism, excretion, and toxicity. Our methodology suggested that compounds with 3,4-dihydroisoquinoline moiety were potentially active in inhibiting leucine aminopeptidase and could be used for further in-depth in vitro and in vivo studies. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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27 pages, 5712 KiB

Open AccessFeature PaperArticle

A Supramolecular Approach to Structure-Based Design with A Focus on Synthons Hierarchy in Ornithine-Derived Ligands: Review, Synthesis, Experimental and in Silico Studies

by Joanna Bojarska, Milan Remko, Martin Breza, Izabela D. Madura, Krzysztof Kaczmarek, Janusz Zabrocki and Wojciech M. Wolf

Molecules 2020, 25(5), 1135; https://doi.org/10.3390/molecules25051135 - 3 Mar 2020

Cited by 46 | Viewed by 8866

Abstract

The success of innovative drugs depends on an interdisciplinary and holistic approach to their design and development. The supramolecular architecture of living systems is controlled by non-covalent interactions to a very large extent. The latter are prone to extensive cooperation and like a virtuoso play a symphony of life. Thus, the design of effective ligands should be based on thorough knowledge on the interactions at either a molecular or high topological level. In this work, we emphasize the importance of supramolecular structure and ligand-based design keeping the potential of supramolecular H-bonding synthons in focus. In this respect, the relevance of supramolecular chemistry for advanced therapies is appreciated and undisputable. It has developed tools, such as Hirshfeld surface analysis, using a huge data on supramolecular interactions in over one million structures which are deposited in the Cambridge Structure Database (CSD). In particular, molecular interaction surfaces are useful for identification of macromolecular active sites followed by in silico docking experiments. Ornithine-derived compounds are a new, promising class of multi-targeting ligands for innovative therapeutics and cosmeceuticals. In this work, we present the synthesis together with the molecular and supramolecular structure of a novel ornithine derivative, namely N-α,N-δ)-dibenzoyl-(α)-hydroxymethylornithine, 1. It was investigated by modern experimental and in silico methods in detail. The incorporation of an aromatic system into the ornithine core induces stacking interactions, which are vital in biological processes. In particular, rare C=O^…π intercontacts have been identified in 1. Supramolecular interactions were analyzed in all structures of ornithine derivatives deposited in the CSD. The influence of substituent was assessed by the Hirshfeld surface analysis. It revealed that the crystal packing is stabilized mainly by H^…O, O^…H, C^…H, Cl (Br, F)^…H and O^…O interactions. Additionally, π^…π, C-H^…π and N-O^…π interactions were also observed. All relevant H-bond energies were calculated using the Lippincott and Schroeder H-bond model. A library of synthons is provided. In addition, the large synthons (Long-Range Synthon Aufbau Module) were considered. The DFT optimization either in vacuo or in solutio yields very similar molecular species. The major difference with the relevant crystal structure was related to the conformation of terminal benzoyl C15-C20 ring. Furthermore, in silico prediction of the extensive physicochemical ADME profile (absorption, distribution, metabolism and excretion) related to the drug-likeness and medicinal chemistry friendliness revealed that a novel ornithine derivative 1 has the potential to be a new drug candidate. It has shown good in silico absorption and very low toxicity. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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19 pages, 4727 KiB

Open AccessArticle

Covalent Inhibition of the Histamine H₃ Receptor

by Gábor Wágner, Tamara A. M. Mocking, Albert J. Kooistra, Inna Slynko, Péter Ábrányi-Balogh, György M. Keserű, Maikel Wijtmans, Henry F. Vischer, Iwan J. P. de Esch and Rob Leurs

Molecules 2019, 24(24), 4541; https://doi.org/10.3390/molecules24244541 - 11 Dec 2019

Cited by 5 | Viewed by 5679

Abstract

Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H₃ receptor (H₃R). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate H₃R ligand 44. It shows high reactivity toward glutathione combined with appropriate stability in water and reacts selectively with the cysteine sidechain in a model nonapeptide equipped with nucleophilic residues. The covalent interaction of 44 with H₃R was validated with washout experiments and leads to inverse agonism on H₃R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H₃R conformation and to study the consequences of prolonged inhibition of the H₃R. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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12 pages, 3434 KiB

Open AccessArticle

A Repurposing Approach for Uncovering the Anti-Tubercular Activity of FDA-Approved Drugs with Potential Multi-Targeting Profiles

by Basem Battah, Giulia Chemi, Stefania Butini, Giuseppe Campiani, Simone Brogi, Giovanni Delogu and Sandra Gemma

Molecules 2019, 24(23), 4373; https://doi.org/10.3390/molecules24234373 - 29 Nov 2019

Cited by 36 | Viewed by 4302

Abstract

Tuberculosis (TB) is one of the top 10 causes of death worldwide. This scenario is further complicated by the insurgence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. The identification of appropriate drugs with multi-target affinity profiles is considered to be a widely accepted strategy to overcome the rapid development of resistance. The aim of this study was to discover Food and Drug Administration (FDA)-approved drugs possessing antimycobacterial activity, potentially coupled to an effective multi-target profile. An integrated screening platform was implemented based on computational procedures (high-throughput docking techniques on the target enzymes peptide deformylase and Zmp1) and in vitro phenotypic screening assays using two models to evaluate the activity of the selected drugs against Mycobacterium tuberculosis (Mtb), namely, growth of Mtb H37Rv and of two clinical isolates in axenic media, and infection of peripheral blood mononuclear cells with Mtb. Starting from over 3000 FDA-approved drugs, we selected 29 marketed drugs for submission to biological evaluation. Out of 29 drugs selected, 20 showed antimycobacterial activity. Further characterization suggested that five drugs possessed promising profiles for further studies. Following a repurposing strategy, by combining computational and biological efforts, we identified marketed drugs with relevant antimycobacterial profiles. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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12 pages, 3730 KiB

Open AccessArticle

Identification of The Fipronil Resistance Associated Mutations in Nilaparvata lugens GABA Receptors by Molecular Modeling

by Yafeng Tian, Ya Gao, Yanming Chen, Genyan Liu and Xiulian Ju

Molecules 2019, 24(22), 4116; https://doi.org/10.3390/molecules24224116 - 14 Nov 2019

Cited by 15 | Viewed by 3091

Abstract

Fipronil, as the first commercialized member of phenylpyrazole insecticides, has been widely used to control planthoppers in China due to its high insecticidal activity and low toxicity to mammals. However, insects have developed resistance to phenylpyrazoles after their long-term use. The resistance mechanism of insects to fipronil has not been well identified, which limited the development of phenylpyrazole insecticides. In the present study, we aimed to elucidate the related fipronil-resistance mechanism in N. lugens GABA receptors by homology modeling, molecular docking, and molecular dynamics. The results indicated that fipronil showed the weakest interaction with the mutant (R0′Q + A2′S) GABA receptors, which is consistent with the experimental study. The binding poses of fipronil were found to be changed when mutations were conducted. These findings verified the novel fipronil-resistance mechanism in silico and provide important information for the design of novel GABAR-targeting insecticides. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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22 pages, 7189 KiB

Open AccessArticle

Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques

by Ashwini Machhindra Londhe, Changdev Gorakshnath Gadhe, Sang Min Lim and Ae Nim Pae

Molecules 2019, 24(22), 4085; https://doi.org/10.3390/molecules24224085 - 12 Nov 2019

Cited by 40 | Viewed by 8652

Abstract

In this study, we investigate the atomistic details of Keap1-Nrf2 inhibitors by in-depth modeling techniques, including molecular dynamics (MD) simulations, and the path-based free energy method of umbrella sampling (US). The protein–protein interaction (PPI) of Keap1-Nrf2 is implicated in several neurodegenerative diseases like cancer, diabetes, and cardiomyopathy. A better understanding of the five sub-pocket binding sites for Nrf2 (ETGE and DLG motifs) inside the Kelch domain would expedite the inhibitor design process. We selected four protein–ligand complexes with distinct co-crystal ligands and binding occupancies inside the Nrf2 binding site. We performed 100 ns of MD simulation for each complex and analyzed the trajectories. From the results, it is evident that one ligand (1VV) has flipped inside the binding pocket, whereas the remaining three were stable. We found that Coulombic (Arg483, Arg415, Ser363, Ser508, and Ser602) and Lennard–Jones (Tyr525, Tyr334, and Tyr572) interactions played a significant role in complex stability. The obtained binding free energy values from US simulations were consistent with the potencies of simulated ligands. US simulation highlight the importance of basic and aromatic residues in the binding pocket. A detailed description of the dissociation process brings valuable insight into the interaction of the four selected protein–ligand complexes, which could help in the future to design more potent PPI inhibitors. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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14 pages, 4355 KiB

Open AccessArticle

Pharmacophoric Site Identification and Inhibitor Design for Autotaxin

by Myeong Hwi Lee, Dae-Yon Lee, Anand Balupuri, Jong-Woo Jeong and Nam Sook Kang

Molecules 2019, 24(15), 2808; https://doi.org/10.3390/molecules24152808 - 1 Aug 2019

Cited by 6 | Viewed by 2990

Abstract

Autotaxin (ATX) is a potential drug target that is associated with inflammatory diseases and various cancers. In our previous studies, we have designed several inhibitors targeting ATX using computational and experimental approaches. Here, we have analyzed topological water networks (TWNs) in the binding pocket of ATX. TWN analysis revealed a pharmacophoric site inside the pocket. We designed and synthesized compounds considering the identified pharmacophoric site. Furthermore, we performed biological experiments to determine their ATX inhibitory activities. High potency of the designed compounds supports the predictions of the TWN analysis. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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12 pages, 3865 KiB

Open AccessArticle

Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening

by Andrea Scarpino, Dávid Bajusz, Matic Proj, Martina Gobec, Izidor Sosič, Stanislav Gobec, György G. Ferenczy and György M. Keserű

Molecules 2019, 24(14), 2590; https://doi.org/10.3390/molecules24142590 - 16 Jul 2019

Cited by 12 | Viewed by 4229

Abstract

Large-scale virtual screening of boronic acid derivatives was performed to identify nonpeptidic covalent inhibitors of the β5i subunit of the immunoproteasome. A hierarchical virtual screening cascade including noncovalent and covalent docking steps was applied to a virtual library of over 104,000 compounds. Then, 32 virtual hits were selected, out of which five were experimentally confirmed. Biophysical and biochemical tests showed micromolar binding affinity and time-dependent inhibitory potency for two compounds. These results validate the computational protocol that allows the screening of large compound collections. One of the lead-like boronic acid derivatives identified as a covalent immunoproteasome inhibitor is a suitable starting point for chemical optimization. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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20 pages, 5454 KiB

Open AccessArticle

Anticancer Function and ROS-Mediated Multi-Targeting Anticancer Mechanisms of Copper (II) 2-hydroxy-1-naphthaldehyde Complexes

by Muhammad Hamid Khan, Meiling Cai, Jungang Deng, Ping Yu, Hong Liang and Feng Yang

Molecules 2019, 24(14), 2544; https://doi.org/10.3390/molecules24142544 - 12 Jul 2019

Cited by 28 | Viewed by 3226 | Correction

Abstract

Multi-targeting of oncoproteins by a single molecule represents an effectual, rational, and an alternative approach to target therapy. We carried out a systematic study to reveal the mechanisms of action of newly synthesized Cu²⁺ compounds of 2-naphthalenol and 1-(((2-pyridinylmethyl)imino)methyl)- (C1 and C2). The antiproliferative activity of the as-synthesized complexes in three human cancer cell lines indicates their potential as multi-targeted antitumor agents. Relatively, C1 and C2 showed better efficacy in vitro relative to Cisplatin and presented promising levels of toxicity against A-549 cells. On the whole, the Cu²⁺ complexes exhibited chemotherapeutic effects by generating reactive oxygen species (ROS) and arresting the cell cycle in the G₀/G₁ phase by competent regulation of cyclin and cyclin-dependent kinases. Fascinatingly, the Cu²⁺ complexes were shown to activate the apoptotic and autophagic pathways in A-549 cells. These complexes effectively induced endoplasmic reticulum stress-mediated apoptosis, inhibited topoisomerase-1, and damaged cancer DNA through a ROS-mediated mechanism. The synthesized Cu²⁺ complexes established ROS-mediated targeting of multiple cell signaling pathways as a fabulous route for the inhibition of cancer cell growth. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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21 pages, 3788 KiB

Open AccessArticle

Dihydropyrazole Derivatives Containing Benzo Oxygen Heterocycle and Sulfonamide Moieties Selectively and Potently Inhibit COX-2: Design, Synthesis, and Anti-Colon Cancer Activity Evaluation

by Xiao-Qiang Yan, Zhong-Chang Wang, Bo Zhang, Peng-Fei Qi, Gui-Gen Li and Hai-Liang Zhu

Molecules 2019, 24(9), 1685; https://doi.org/10.3390/molecules24091685 - 30 Apr 2019

Cited by 16 | Viewed by 3343

Abstract

Cyclooxygenase-2 (COX-2) as a rate-limiting metabolism enzyme of arachidonic acid has been found to be implicated in tumor occurrence, angiogenesis, metastasis as well as apoptosis inhibition, regarded as an attractive therapeutic target for cancer therapy. In our research, a series of dihydropyrazole derivatives containing benzo oxygen heterocycle and sulfonamide moieties were designed as highly potent and selective COX-2 inhibitors by computer-aided drug analysis of known COX-2 inhibitors. A total of 26 compounds were synthesized and evaluated COX-2 inhibition and pharmacological efficiency both in vitro and in vivo with multi-angle of view. Among them, compound 4b exhibited most excellent anti-proliferation activities against SW620 cells with IC₅₀ of 0.86 ± 0.02 µM than Celecoxib (IC₅₀ = 1.29 ± 0.04 µM). The results favored our rational design intention and provides compound 4b as an effective COX-2 inhibitor available for the development of colon tumor therapeutics. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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Review

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17 pages, 3379 KiB

Open AccessReview

Targeting Trypanothione Reductase, a Key Enzyme in the Redox Trypanosomatid Metabolism, to Develop New Drugs against Leishmaniasis and Trypanosomiases

by Theo Battista, Gianni Colotti, Andrea Ilari and Annarita Fiorillo

Molecules 2020, 25(8), 1924; https://doi.org/10.3390/molecules25081924 - 21 Apr 2020

Cited by 75 | Viewed by 5347

Abstract

The protozoans Leishmania and Trypanosoma, belonging to the same Trypanosomatidae family, are the causative agents of Leishmaniasis, Chagas disease, and human African trypanosomiasis. Overall, these infections affect millions of people worldwide, posing a serious health issue as well as socio-economical concern. Current treatments are inadequate, mainly due to poor efficacy, toxicity, and emerging resistance; therefore, there is an urgent need for new drugs. Among several molecular targets proposed, trypanothione reductase (TR) is of particular interest for its critical role in controlling the parasite’s redox homeostasis and several classes of active compounds that inhibit TR have been proposed so far. This review provides a comprehensive overview of TR’s structural characterization. In particular, we discuss all the structural features of TR relevant for drug discovery, with a focus on the recent advances made in the understanding of inhibitor binding. The reported cases show how, on the basis of the detailed structural information provided by the crystallographic analysis, it is possible to rationally modify molecular scaffolds to improve their properties. Full article

(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)

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