Discovery of Potent, Reversible, and Competitive Cruzain Inhibitors with Trypanocidal Activity: A Structure-Based Drug Design Approach

Autor(es):Mostrar menos -

de Souza, Mariana L. ^[1] ; Rezende Junior, Celso de Oliveira ^[2] ; Ferreira, Rafaela S. ^[3] ; Espinoza Chavez, Rocio Marisol ^[2] ; Ferreira, Leonardo L. G. ^[1] ; Slafer, Brian W. ^[2] ; Magalhaes, Luma G. ^[1] ; Krogh, Renata ^[1] ; Oliva, Glaucius ^[1] ; Cruz, Fabio Cardoso ^[4] ; Dias, Luiz Carlos ^[2] ; Andricopulo, Adriano D. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Phys Inst Sao Carlos, Lab Med & Computat Chem, BR-13563120 Sao Carlos, SP - Brazil

^[2] Univ Estadual Campinas, Inst Chem, BR-13084971 Campinas, SP - Brazil

^[3] Univ Fed Minas Gerais, Dept Biochem & Immunol, BR-31270901 Belo Horizonte, MG - Brazil

^[4] Univ Fed Sao Paulo, Dept Pharmacol, BR-04023062 Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 60, n. 2, p. 1028-1041, FEB 2020.
• Citações Web of Science: 1

Resumo

A virtual screening conducted with nearly 4 000 000 compounds from lead-like and fragment-like subsets enabled the identification of a small-molecule inhibitor (1) of the Trypanosoma cruzi cruzain enzyme, a validated drug target for Chagas disease. Subsequent comprehensive structure-based drug design and structure-activity relationship studies led to the discovery of carbamoyl imidazoles as potent, reversible, and competitive cruzain inhibitors. The most potent carbamoyl imidazole inhibitor (45) exhibited high affinity with a K-i value of 20 nM, presenting both in vitro and in vivo activity against T. cruzi. Furthermore, the most promising compounds reduced parasite burden in vivo and showed no toxicity at a dose of 100 mg/kg. These carbamoyl imidazoles are structurally attractive, nonpeptidic, and easy to prepare and synthetically modify. Finally, these results further advance our understanding of the noncovalent mode of inhibition of this pharmaceutically relevant enzyme, building strong foundations for drug discovery efforts. (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