Abordagem computacional para a descoberta de novos inibidores de prolil oligopeptidase 80 de Trypanosoma cruzi

Abstract

Chagas disease is a serious infectious disease caused by the trypanosomatid parasite Trypanosoma cruzi. Currently, the benznidazole is the only drug available for treating the disease. However, due to the emergence of benznidazole-resistant parasites, low efficacy in the chronic phase and considerable number of adverse effects, the discovery of new drugs more effective, safer and with innovative mechanism of action is imperative. In this context, the general objective of this work was to identify inhibitors of the enzyme prolyl oligopeptidase 80 (POPTc80), a validated target for Trypanosoma cruzi, using computational methods based on the structure of the target (SBDD) and ligand (LBDD). Initially, the three-dimensional structure of POPTc80 was predicted using three different approaches. After structural refinement and validation, the best 3D structure, obtained from the AlphaFold server, was submitted to structural analysis. In this step, three representative conformations of POPTc80 generated on the DynOmics server were selected using Principal Component Analysis (PCA). These structures were then used as structural bases for the construction and validation of molecular docking protocols in the Glide program. Molecular anchoring demonstrated that the conformation 3 results showed the highest rate of enrichment during screening of a set of active compounds and decoys. Then, the docking poses for POPTc80 inhibitors described in the literature were considered queries for generating and validating shape-based models in the vROCS program. As a result, a 3D structure of the POPTc80 was possible, a validated docking protocol was developed and a specific shape-based model for POPTc80 was also developed. At the end of this process, the best molecular docking protocols and the best shape-based model were used as computational filters for the virtual screening of the ChemBridge library, which made it possible to obtain a set of putative hits that will be experimentally validated in the POPTc80 enzyme in collaboration.