Structural analysis and shape-based identification of novel inhibitors targeting the Trypanosoma cruzi proteasome.

There is an urgent need to develop new, safer, and more effective drugs against Chagas disease (CD) as well as related kinetoplastid diseases. Targeting and inhibiting the Trypanosoma cruzi proteasome has emerged as a promising therapeutic approach in this context. To expand the chemical space for this class of inhibitors, we performed virtual screening campaigns with emphasis on shape-based similarity and ADMET prioritization. We describe the ideation and application of robustly validated shape queries for these campaigns, which furnished 44 compounds for biological evaluation. Five hit compounds demonstrated in vitro antitrypanosomal activity by potential inhibition of T. cruzi proteasome and notable chemical diversities, particularly, LCQFTC11. Structural insights were achieved by homology modeling, sequence/structure alignment, proteasome-species comparison, docking, molecular dynamics, and MMGBSA binding affinity estimations. These methods confirmed key interactions as well as the stability of LCQFTC11 at the β4/β5 subunits' binding site of the T. cruzi proteasome, consistent with known inhibitors. Our results warrant future assay confirmation of our hit as a T. cruzi proteasome inhibitor. Importantly, we also shed light into dynamic details for a proteasome inhibition mechanism that shall be further investigated. We expect to contribute to the development of viable CD drug candidates through such a relevant approach. • T. cruzi proteasome inhibition is a promising therapeutic approach for Chagas disease • Shape-based virtual screening to expand the chemical space of T. cruzi proteasome inhibitors • 44 compounds tested in vitro , from which 5 hits showed EC 50 < 50 μM; particularly, LCQFTC11 with EC 50 = 8.15 μM and high SI • Structural analysis by homology model, sequence/structure alignment/comparison, docking, molecular dynamics, and MMGBSA • Hypotheses onto dynamic details for a proteasome inhibition mechanism [ABSTRACT FROM AUTHOR]