The design and inhibitory profile of new benzimidazole derivatives against triosephosphate isomerase from Trypanosoma cruzi: A problem of residue motility

To develop a new set of compounds with inhibitory activity against the triosephosphate isomerase of Trypanosoma cruzi (TcTIM), a group of benzimidazole derivatives was studied using four different docking procedures. These docking procedures differ in the number and type of mobile residues considered in the analysis. As a result of this methodology, a clustered analysis of plausible candidate structures was produced. A different set of previously synthesized compounds was used to validate this analysis. The validation showed that the best results correspond to the docking procedure in which the residues near the hydrophobic pocket of the protein's interface were considered mobile. A binding site for the best candidates was identified. Residues Tyr103, Glu105 and Lys113, among others, are important for the binding of this kind of compound. Residue Tyr103 is different in the human TIM, thus establishing a key feature for the future design of selective inhibitors.

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► Blocking the glycolitic pathway in Trypanosoma cruzi is target for drug discovery.
► Some benzoazoles have been evaluated as inhibitors of triosephosphate isomerase.
► Flexible–flexible docking of benzoazoles and clustered analyses were performed.
► The binding site and interaction with clustered analyses of dockings were identified.
► An alternative mode of action is also proposed as a result of these studies.