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

Autor(es)

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.

• Tipo de documento: Artigo Científico
• Fonte: Future Medicinal Chemistry; v. 9, n. 7, p. 641-657, MAY 2017.
• Citações Web of Science: 8

Resumo

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)

• Processo FAPESP: 11/13789-6 - Planejamento de Inibidores da Enzima Cruzaína Candidatos a Fármacos para o Tratamento da Doença de Chagas
• Beneficiário: Ivaní Pauli
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 13/25658-9 - Planejamento e Desenvolvimento de Candidatos a Fármacos para a Doença de Chagas
• Beneficiário: Leonardo Luiz Gomes Ferreira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado