Identification of novel thiadiazin derivatives as potentially selective inhibitors towards trypanothione reductase from Trypanosoma cruzi by molecular docking using the numerical index poses ratio Pr and the binding mode analysis

摘要

Chagas disease is a serious health problem in Central and South America for which effective treatment is not currentlyavailable. This illness is caused by the protozoa Trypanosoma cruzi, a species that relies on a thiol-based metabolism toregulate oxidative stress. Trypanothione reductase enzyme plays a central role in the metabolic pathway of the parasite. Inthis work, a virtual screening of a library of novel thiadiazine derivatives against trypanothione reductase using moleculardocking was performed. Four different series of hybrid ligands having in the structure one or two peptoid moieties(series Ⅰ and Ⅱ) or the tetrazole ring (series Ⅲ and Ⅳ) were considered. An ad hoc numerical index called poses ratio wasintroduced to interpret the results of the docking analysis and to establish relevant structure-interaction relationships. Inaddition, six binding modes were found for the ligands with the highest populated conformational clusters after applyingcontact-based analysis. The most regular and relevant were binding modes I and II, found mainly for ligands from series I.A subsequent molecular docking on human glutathione reductase enzyme allowed to assess the possible cytotoxicity ofthe ligands towards human cells. A selective binding profile was found for ligands with interactions in the Hydrophobiccleft, the spermidine and the Z subsites inside the active site of trypanothione reductase. At the end of the study, newthiadiazine-based compounds were identified as plausible candidates to selectively inhibit the parasitic enzyme.