Development of a pharmacophore for cruzain using oxadiazoles as virtual molecular probes: quantitative structure-activity relationship studies

Autor(es)

de Souza, Anacleto S. ^[1] ; de Oliveira, Marcelo T. ^{[2, 1]} ; Andricopulo, Adriano D. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Lab Quim Med & Computac, Ctr Pesquisa & Inovacao Biodivers & Farmacos, BR-13563120 Sao Carlos, SP - Brazil

^[2] Univ Sao Paulo, Inst Quim Sao Carlos, Ave Trabalhador Sao Carlense 400, BR-13566590 Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Computer-Aided Molecular Design; v. 31, n. 9, p. 801-816, SEP 2017.
• Citações Web of Science: 2

Resumo

Chagas's is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. According to the World Health Organization, 7 million people are infected worldwide leading to 7000 deaths per year. Drugs available, nifurtimox and benzimidazole, are limited due to low efficacy and high toxicity. As a validated target, cruzain represents a major front in drug discovery attempts for Chagas disease. Herein, we describe the development of 2D QSAR ( = 0.81) and a 3D-QSAR-based pharmacophore ( = 0.82) from a series of non-covalent cruzain inhibitors represented mostly by oxadiazoles (lead compound, IC50 = 200 nM). Both models allowed us to map key intermolecular interactions in S1', S2 and S3 cruzain sub-sites (including halogen bond and CaEuro'H/pi). To probe the predictive capacity of obtained models, inhibitors available in the literature from different classes displaying a range of scaffolds were evaluate achieving mean absolute deviation of 0.33 and 0.51 for 2D and 3D models, respectively. CoMFA revealed an unexplored region where addition of bulky substituents to produce new compounds in the series could be beneficial to improve biological activity. (AU)

• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs