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Juárez-Saldivar, A.* ; Schroeder, M.* ; Salentin, S.* ; Haupt, V.J.* ; Saavedra, E.* ; Vázquez, C.* ; Reyes-Espinosa, F.* ; Herrera-Mayorga, V.* ; Villalobos-Rocha, J.C.* ; Garcia Perez, C. ; Campillo, N.E.* ; Rivera, G.*

Computational drug repositioning for chagas disease using protein-ligand interaction profiling.

Int. J. Mol. Sci. 21:4270 (2020)

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Chagas disease, caused byTrypanosoma cruzi(T. cruzi), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (HsDHFR) inhibitors such as trimetrexate also inhibitT. cruziDHFR-TS (TcDHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for newTcDHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities againstT. cruziinfection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity toTcDHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putativeTcDHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested onT. cruziepimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Antiprotozoal ; Chagas Disease ; Fda-drugs ; Molecular Docking ; Protein-ligand Interaction Profiler ; Repositioning; Reductase-thymidylate Synthase; Trypanosoma-cruzi; In-vitro; Inhibitors; Discovery; Identification; Imatinib; Targets; Growth; Potent

ISSN (print) / ISBN 1422-0067

e-ISSN 1661-6596

Journal International Journal of Molecular Sciences

Quellenangaben Volume: 21, Issue: 12, Article Number: 4270

Publisher MDPI

Publishing Place Basel

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)