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

• Published in: European journal of medicinal chemistry Vol. 257; p. 115498
• Main Authors: Santos, Viviane Corrêa, Leite, Paulo Gaio, Santos, Lucianna Helene, Pascutti, Pedro Geraldo, Kolb, Peter, Machado, Fabiana Simão, Ferreira, Rafaela Salgado
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-09-2023
• Subjects: Chagas disease; Cruzain; Cruzipains; Docking; Molecular dynamics simulations; Virtual screening; Cruzipains; Chagas disease; Virtual screening; Cruzain; Docking; Molecular dynamics simulations
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115498

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 Ki of 4.6 μM. Then, aided by molecular dynamics simulations, cheminformatics, and docking, we identified the analog compound 22 with a Ki 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.
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•Structure-based techniques aided the discovery of isoquinoline cruzain inhibitors.•8 is a more potent cruzain inhibitor (Ki 4.6 μM) than 22 (Ki 27 μM).•8 and 22 have different profiles for their anti-T. cruzi activity.