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Comput Biol Chem ; 79: 36-47, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30710804

ABSTRACT

Trypanosoma cruzi Trypanothione Reductase (TcTR) is one of the therapeutic targets studied in the development of new drugs against Chagas' disease. Due to its biodiversity, Brazil has several compounds of natural origin that were not yet properly explored in drug discovery. Therefore, we employed the Virtual Screening against TcTR aiming to discover new inhibitors from the Natural Products Database of the Bahia Semi-Arid region (NatProDB). This database has a wide chemical diversity favoring the discovery of new chemical entities. Subsequently, we analyzed the best docking conformations using self-organizing maps (AuPosSOM) aiming to verify their interaction sites at TcTR. Finally, the Pred-hERG, the Aggregator Advisor, the FAF-DRUGS and the pkCSM results allowed us to evaluate, respectively, the cardiotoxicity, aggregation capacity, presence of false positives (PAINS) and its toxicity. Thus, we selected three molecules that could be tested in in vitro assays in the hope that the computational results reported here would favor the development of new anti-chagasic drugs.


Subject(s)
Antiprotozoal Agents/pharmacology , Biological Products/pharmacology , Computer Simulation , Databases, Chemical , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , NADH, NADPH Oxidoreductases/antagonists & inhibitors , Trypanosoma cruzi/drug effects , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Brazil , Chagas Disease/drug therapy , Chagas Disease/metabolism , Chagas Disease/parasitology , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Ligands , Models, Molecular , Molecular Structure , NADH, NADPH Oxidoreductases/metabolism , Parasitic Sensitivity Tests , Structure-Activity Relationship , Trypanosoma cruzi/enzymology
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