Homology Modeling and Molecular Dynamics Simulations of Trypanosoma cruzi Phosphodiesterase b1

Chem Biodivers. 2021 Nov 23. doi: 10.1002/cbdv.202100712. Online ahead of print.

Abstract

Cyclic nucleotide phosphodiesterases have been implicated in the proliferation, differentiation and osmotic regulation of trypanosomatids; in some trypanosomatid species, they have been validated as molecular targets for the development of new therapeutic agents. Because the experimental structure of TcrPDEb1 has not been solved so far, an homology model of the target was created using as template the structure of a TbrPDEb1. The model was refined by extensive enhanced sampling molecular dynamics simulations, and representative snapshots were extracted from the trajectory by combined clustering analysis. This structural ensemble was used to develop a structure-based docking model of the target. The docking accuracy of the model was validated by redocking and cross-docking experiments using all available crystal structures of TbrPDEb1, whereas the scoring accuracy was validated through a retrospective screen, using a carefully curated dataset of compound assayed against TbrPDEb1 and/or TcrPDEb1. Considering the results from in silico validations, the model may be applied in prospective virtual screening campaigns to identify novel hits, as well as to guide the rational design of potent and selective inhibitors targeting this enzyme.

Keywords: Molecular Docking, Molecular dynamics, Phosphodiesterase, Trypanosoma cruzi, Chagas disease.