{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T07:46:17Z","timestamp":1772783177466,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2019,9,4]],"date-time":"2019-09-04T00:00:00Z","timestamp":1567555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo de Investigaci\u00f3n en Salud, Instituto Mexicano del Seguro Social","award":["FIS\/IMSS\/PROT\/G16\/1618"],"award-info":[{"award-number":["FIS\/IMSS\/PROT\/G16\/1618"]}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","award":["251726."],"award-info":[{"award-number":["251726."]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Leishmanicidal drugs have many side effects, and drug resistance to all of them has been documented. Therefore, the development of new drugs and the identification of novel therapeutic targets are urgently needed. Leishmania mexicana trypanothione reductase (LmTR), a NADPH-dependent flavoprotein oxidoreductase important to thiol metabolism, is essential for parasite viability. Its absence in the mammalian host makes this enzyme an attractive target for the development of new anti-Leishmania drugs. Herein, a tridimensional model of LmTR was constructed and the molecular docking of 20 molecules from a ZINC database was performed. Five compounds (ZINC04684558, ZINC09642432, ZINC12151998, ZINC14970552, and ZINC11841871) were selected (docking scores \u221210.27 kcal\/mol to \u22125.29 kcal\/mol and structurally different) and evaluated against recombinant LmTR (rLmTR) and L. mexicana promastigote. Additionally, molecular dynamics simulation of LmTR-selected compound complexes was achieved. The five selected compounds inhibited rLmTR activity in the range of 32.9% to 40.1%. The binding of selected compounds to LmTR involving different hydrogen bonds with distinct residues of the molecule monomers A and B is described. Compound ZINC12151998 (docking score \u221210.27 kcal\/mol) inhibited 32.9% the enzyme activity (100 \u00b5M) and showed the highest leishmanicidal activity (IC50 = 58 \u00b5M) of all the selected compounds. It was more active than glucantime, and although its half-maximal cytotoxicity concentration (CC50 = 53 \u00b5M) was higher than that of the other four compounds, it was less cytotoxic than amphotericin B. Therefore, compound ZINC12151998 provides a promising starting point for a hit-to-lead process in our search for new anti-Leishmania drugs that are more potent and less cytotoxic.<\/jats:p>","DOI":"10.3390\/molecules24183216","type":"journal-article","created":{"date-parts":[[2019,9,5]],"date-time":"2019-09-05T03:22:36Z","timestamp":1567653756000},"page":"3216","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Leishmania mexicana Trypanothione Reductase Inhibitors: Computational and Biological Studies"],"prefix":"10.3390","volume":"24","author":[{"given":"F\u00e9lix","family":"Matadamas-Mart\u00ednez","sequence":"first","affiliation":[{"name":"Departamento de Farmacia, Facultad de Qu\u00edmica, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"},{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Enfermedades Infecciosas y Parasitarias, Unidad M\u00e9dica de Alta Especialidad-Hospital de Pediatr\u00eda, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia","family":"Hern\u00e1ndez-Campos","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia, Facultad de Qu\u00edmica, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfredo","family":"T\u00e9llez-Valencia","sequence":"additional","affiliation":[{"name":"Facultad de Medicina y Nutrici\u00f3n, Universidad Ju\u00e1rez del Estado de Durango Av. Universidad y Fanny Anit\u00faa S\/N, Durango 34000, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandra","family":"V\u00e1zquez-Raygoza","sequence":"additional","affiliation":[{"name":"Facultad de Medicina y Nutrici\u00f3n, Universidad Ju\u00e1rez del Estado de Durango Av. Universidad y Fanny Anit\u00faa S\/N, Durango 34000, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Compar\u00e1n-Alarc\u00f3n","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Enfermedades Infecciosas y Parasitarias, Unidad M\u00e9dica de Alta Especialidad-Hospital de Pediatr\u00eda, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili\u00e1n","family":"Y\u00e9pez-Mulia","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Enfermedades Infecciosas y Parasitarias, Unidad M\u00e9dica de Alta Especialidad-Hospital de Pediatr\u00eda, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8675-5671","authenticated-orcid":false,"given":"Rafael","family":"Castillo","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia, Facultad de Qu\u00edmica, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pntd.0006969","article-title":"Identification and binding mode of novel Leishmania Trypanothione reductase inhibitor from high throughput screening","volume":"12","author":"Turcano","year":"2018","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s00204-009-0485-0","article-title":"Genotoxic effects of the antileishmanial drug Glucantime","volume":"84","author":"Lima","year":"2010","journal-title":"Arch. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/AAC.02360-16","article-title":"Meglumine Antimoniate (Glucantime) Causes Oxidative Stress-Derived DNA Damage in BALB\/c Mice Infected by Leishmania (Leishmania) infantum","volume":"61","author":"Moreira","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.ejmech.2018.08.012","article-title":"An update on small molecule strategies targeting leishmaniasis","volume":"157","author":"Kapil","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12639-010-0006-3","article-title":"Drug targets in Leishmania","volume":"34","author":"Chawla","year":"2010","journal-title":"J. Parasit. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.exppara.2017.11.009","article-title":"In vitro activity of new N-benzyl-1H-benzimidazol-2-amine derivatives against cutaneous, mucocutaneous and visceral Leishmania species","volume":"184","author":"Castillo","year":"2018","journal-title":"Exp. Parasitol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.pep.2004.12.012","article-title":"Expression, purification, and characterization of Leishmania donovani trypanothione reductase in Escherichia Coli","volume":"40","author":"Mittal","year":"2005","journal-title":"Protein Expr. Purif."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.4155\/fmc.13.146","article-title":"Structural insights into the enzymes of the trypanothione pathway: Targets for antileishmaniasis drugs","volume":"5","author":"Colotti","year":"2013","journal-title":"Future Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1002\/cmdc.200900262","article-title":"Investigation of trypanothione reductase as a drug target in Trypanosoma brucei","volume":"4","author":"Spinks","year":"2009","journal-title":"Chem. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1016\/j.bmc.2005.11.004","article-title":"Time-dependent inhibitors of trypanothione reductase: Analogues of the spermidine alkaloid lunarine and related natural products","volume":"14","author":"Hamilton","year":"2006","journal-title":"Bioorg. Med. Chem."},{"key":"ref_11","first-page":"939","article-title":"Trypanothione Reductase: A Target for the Development of Anti- Trypanosoma cruzi Drugs","volume":"17","author":"Paulino","year":"2017","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1016\/j.bmcl.2006.11.090","article-title":"Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening","volume":"17","author":"Holloway","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1002\/cmdc.201300276","article-title":"Metal-based compounds as prospective antileishmanial agents: Inhibition of trypanothione reductase by selected gold complexes","volume":"8","author":"Colotti","year":"2013","journal-title":"Chem. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00726-011-0997-9","article-title":"A gold-containing drug against parasitic polyamine metabolism: The X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition","volume":"42","author":"Ilari","year":"2012","journal-title":"Amino. Acids"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1021\/jm900185q","article-title":"Molecular basis of antimony treatment in leishmaniasis","volume":"52","author":"Baiocco","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1080\/14756366.2016.1250755","article-title":"Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives","volume":"32","author":"Saccoliti","year":"2017","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1002\/cmdc.201300176","article-title":"Inhibition of Leishmania infantum trypanothione reductase by azole-based compounds: A comparative analysis with its physiological substrate by X-ray crystallography","volume":"8","author":"Baiocco","year":"2013","journal-title":"Chem. Med. Chem."},{"key":"ref_18","first-page":"2960","article-title":"Insights about resveratrol analogues against trypanothione reductase of Leishmania braziliensis: Molecular modeling, computational docking and in vitro antileishmanial studies","volume":"37","author":"Machado","year":"2018","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s10822-016-9921-4","article-title":"Drug search for leishmaniasis: A virtual screening approach by grid computing","volume":"30","author":"Ochoa","year":"2016","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1093\/nar\/gkp322","article-title":"QMEAN server for protein model quality estimation","volume":"37","author":"Benkert","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/0263-7855(90)80070-V","article-title":"WHAT IF: A molecular modeling and drug design program","volume":"8","author":"Vriend","year":"1990","journal-title":"J. Mol. Graph."},{"key":"ref_22","unstructured":"DeLano, W.L. (2002). The PyMOL Molecular Graphics System, DeLano Scientific LLC."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0969-2126(99)80011-2","article-title":"Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors","volume":"7","author":"Bond","year":"1999","journal-title":"Structure"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1007\/s00436-014-3850-8","article-title":"Anti-Trypanosoma cruzi and anti-leishmanial activity by quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives","volume":"113","author":"Palos","year":"2014","journal-title":"Parasitol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1080\/07391102.2015.1085904","article-title":"Developing imidazole analogues as potential inhibitor for Leishmania donovani trypanothione reductase: Virtual screening, molecular docking, dynamics and ADMET approach","volume":"33","author":"Pandey","year":"2015","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"38","DOI":"10.4103\/0972-9062.112533","article-title":"Molecular modeling, structural analysis and identification of ligand binding sites of trypanothione reductase from Leishmania mexicana","volume":"50","author":"Mutlu","year":"2013","journal-title":"J. Vector Borne Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"29493","DOI":"10.1074\/jbc.M403187200","article-title":"Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: A template for drug design","volume":"279","author":"Saravanamuthu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6514","DOI":"10.1021\/jm200312v","article-title":"Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: Discovery, synthesis, and characterization of their binding mode by protein crystallography","volume":"54","author":"Patterson","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"161","DOI":"10.3109\/14756369709029312","article-title":"Rational design of selective ligands for trypanothione reductase from Trypanosoma cruzi. Structural effects on the inhibition by dibenzazepines based on imipramine","volume":"12","author":"Garforth","year":"1997","journal-title":"J. Enzym. Inhib."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1093\/nar\/gku316","article-title":"Deciphering key features in protein structures with the new ENDscript server","volume":"42","author":"Robert","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhang, Y. (2008). I-TASSER server for protein 3D structure prediction. BMC Bioinform., 9.","DOI":"10.1186\/1471-2105-9-40"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1093\/nar\/gku340","article-title":"SWISS-MODEL: Modelling protein tertiary and quaternary structure using evolutionary information","volume":"42","author":"Biasini","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nprot.2015.053","article-title":"The Phyre web portal for protein modeling, prediction and analysis","volume":"10","author":"Kelley","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1002\/prot.22711","article-title":"Improved side-chain torsion potentials for the Amber ff99SB protein force field","volume":"78","author":"Piana","year":"2010","journal-title":"Proteins"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: Fast, flexible, and free","volume":"26","author":"Lindahl","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_36","first-page":"1","article-title":"Using ZINC to acquire a virtual screening library","volume":"14","author":"Irwin","year":"2008","journal-title":"Curr. Protoc. Bioinformatics"},{"key":"ref_37","unstructured":"(2014). Maestro, version 9.6, Schr\u00f6dinger, LLC."},{"key":"ref_38","first-page":"57","article-title":"Python: A programming language for software integration and development","volume":"17","author":"Sanner","year":"1999","journal-title":"J. Mol. Graph. Model."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3181","DOI":"10.1016\/S0040-4039(01)94977-9","article-title":"A new model for calculating atomic charges in molecules","volume":"19","author":"Gasteiger","year":"1978","journal-title":"Tetrahedron Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.1007\/s00436-018-5944-1","article-title":"Giardia lamblia: Identification of molecules that contribute to direct mast cell activation","volume":"117","year":"2018","journal-title":"Parasitol. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1111\/j.1432-1033.1994.tb18740.x","article-title":"Mechanism of inhibition of trypanothione reductase and glutathione reductase by trivalent organic arsenials","volume":"221","author":"Cunningham","year":"1994","journal-title":"Eur. J. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.1432-1033.1989.tb14643.x","article-title":"Trypanothione reductase from Trypanosoma cruzi. Catalytic properties of the enzyme and inhibition studies with trypanocidal compounds","volume":"180","author":"Schirmer","year":"1989","journal-title":"Eur. J. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1021\/ja01318a036","article-title":"The determination of enzyme dissociation constants","volume":"56","author":"Lineweaver","year":"1934","journal-title":"J. Am. Chem. Soc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1107\/S0907444904011679","article-title":"PRODRG: A tool for high-throughput crystallography of protein\u2013ligand complexes","volume":"60","year":"2004","journal-title":"Acta. Cryst. D. Biol. Cryst."},{"key":"ref_45","first-page":"397","article-title":"The GROMOS software package for biomolecular simulations","volume":"95","author":"Scott","year":"1995","journal-title":"METECC"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1080\/00268978800101881","article-title":"An analysis of the accuracy of Langevin and molecular dynamics algorithms","volume":"65","author":"Pastor","year":"1988","journal-title":"Mol. Phys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3658","DOI":"10.1093\/bioinformatics\/btx491","article-title":"FAF-Drugs4: Free ADME-tox filtering computations for chemical biology and early stages drug discovery","volume":"33","author":"Lagorce","year":"2017","journal-title":"Bioinformatics."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1021\/ci500588j","article-title":"DataWarrior: An open-source program for chemistry aware data visualization and analysis","volume":"55","author":"Sander","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1093\/nar\/gku401","article-title":"ProTox: A web server for the in silico prediction of rodent oral toxicity","volume":"42","author":"Drwal","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.mimet.2012.01.013","article-title":"A fluorometric method for evaluation of pharmacological activity against intracellular Leishmania amastigotes","volume":"89","year":"2012","journal-title":"J. Microbiol. Methods"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/18\/3216\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:16:40Z","timestamp":1760188600000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/18\/3216"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,4]]},"references-count":51,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["molecules24183216"],"URL":"https:\/\/doi.org\/10.3390\/molecules24183216","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,4]]}}}