Structure-based discovery of novel cruzain inhibitors with distinct trypanocidal activity profiles

Abstract

Over 110 years after the first formal description of Chagas disease, the trypanocidal drugs thus far available have limited efficacy and several side effects. This encourages the search for novel treatments that inhibit T. cruzi targets. One of the most studied anti-T. cruzi targets is the cysteine protease cruzain; it is associated with metacyclogenesis, replication, and invasion of the host cells. We used computational techniques to identify novel molecular scaffolds that act as cruzain inhibitors. First, with a docking-based virtual screening, we identified compound 8, a competitive cruzain inhibitor with a K_i of 4.6 μM. Then, aided by molecular dynamics simulations, cheminformatics, and docking, we identified the analog compound 22 with a K_i of 27 μM. Surprisingly, despite sharing the same isoquinoline scaffold, compound 8 presented higher trypanocidal activity against the epimastigote forms, while compound 22, against the trypomastigotes and amastigotes. Taken together, compounds 8 and 22 represent a promising scaffold for further development of trypanocidal compounds as drug candidates for treating Chagas disease.

Keywords: Chagas disease; Cruzain; Cruzipains; Docking; Molecular dynamics simulations; Virtual screening.