Fragment-Based QSAR and Structural Analysis of a Series of Hydroxyethylamine Derivatives as HIV-1 Protease Inhibitors

Autor(es)

Ferreira, Leonardo G. ^[1] ; Andricopulo, Adriano D. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Fis Sao Carlos, Ctr Pesquisa & Inovacao Biodiversidade & Farm, Lab Quim Med & Computac, BR-13563120 Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING; v. 18, n. 5, p. 464-475, 2015.
• Citações Web of Science: 4

Resumo

HIV-1 protease is a key enzyme for viral maturation because it cleaves precursor polypeptides into mature structural and functional proteins. The introduction of protease inhibitors into therapy in the mid-1990s has dramatically changed the AIDS panorama worldwide. However, resistance to currently available protease inhibitors remains a serious challenge that must be overcome. Herein, we report a fragment-based QSAR study of a series of highly potent HIV-1 protease inhibitors, as well as the structural basis of their binding affinity. Hologram QSAR (HQSAR) analyses were performed, resulting in robust statistical models that consistently correlated the bioactivity profile with the two-dimensional molecular descriptors. The robustness of the best model was assessed based on the correlation coefficients (q(2) = 0.70 and r(2) = 0.90), as well as the prediction of the activity of an external test set (r(2) pred = 0.75). Structure-based molecular modeling studies were performed to investigate the binding mode of the best inhibitor in the active site of the enzyme. The HQSAR model and the structural findings provide valuable insights for the rational design of structurally related HIV-1 protease inhibitors. (AU)

• 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