Molecular modeling and structure-activity relationships for a series of benzimidazole derivatives as cruzain inhibitors

Author(s)

Pauli, Ivani ; Ferreira, Leonardo G. ; de Souza, Mariana L. ; Oliva, Glaucius ; Ferreira, Rafaela S. ; Dessoy, Marco A. ; Slafer, Brian W. ; Dias, Luiz C. ; Andricopulo, Adriano D.

• Document type: Journal article
• Source: Future Medicinal Chemistry; v. 9, n. 7, p. 641-657, MAY 2017.
• Web of Science Citations: 8

Abstract

Aim: Chagas disease is endemic in Latin America and no effective treatment is available. Efforts in drug research have focused on several enzymes from Trypanosoma cruzi, among which cruzain is a validated pharmacological target. Methodology: Chemometric analyses were performed on the data set using the hologram quantitative structure-activity relationship, comparative molecular field analysis and comparative molecular similarity index analysis methods. Docking simulations were executed using the crystallographic structure of cruzain in complex with a benzimidazole inhibitor. The top-scoring enzyme-inhibitor complexes were selected for the development of the 3D quantitative structure-activity relationship (QSAR) models and to assess the inhibitor binding modes and intermolecular interactions. Results: Benzimidazole derivatives as cruzain inhibitors were used in molecular docking and QSAR studies. Significant statistical indicators were obtained, and the best models demonstrated high predictive ability for an external test set (r2pred = 0.65, 0.94 and 0.82 for hologram QSAR, comparative molecular field analysis and comparative molecular similarity index analysis, respectively). Additionally, the graphical information of the chemometric analyses demonstrated substantial complementarity with the enzyme-binding site. Conclusion: These results demonstrate the relevance of the QSAR models to guide the design of structurally related benzimidazole derivatives with improved potency. (AU)

• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 13/25658-9 - Design and development of drug candidates for Chagas Disease
• Grantee: Leonardo Luiz Gomes Ferreira
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 11/13789-6 - Design of inhibitors of the enzyme cruzain as drug candidates for the treatment of Chagas Disease
• Grantee: Ivaní Pauli
• Support type: Scholarships in Brazil - Doctorate