Evaluating QM/MM Free Energy Surfaces for Ranking Cysteine Protease Covalent Inhibitors

Autor(es)

da Costa, Clauber H. S. ^[1] ; Bonatto, Vinicius ^[2] ; dos Santos, Alberto M. ^[1] ; Lameira, Jeronimo ^{[2, 1]} ; Leitao, Andrei ^[2] ; Montanari, Carlos A. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Fed Para, Lab Planejamento & Desenvolvimento Farmacos, BR-66075110 Belem, Para - Brazil

^[2] Univ Sao Paulo, Grp Med, NEQUIMED, IQSC, BR-13566590 Sao Carlos - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 60, n. 2, p. 880-889, FEB 2020.
• Citações Web of Science: 1

Resumo

One tactic for cysteine protease inhibition is to form a covalent bond between an electrophilic atom of the inhibitor and the thiol of the catalytic cysteine. In this study, we evaluate the reaction free energy obtained from a hybrid quantum mechanical/molecular mechanical (QM/MM) free energy profile as a predictor of affinity for reversible, covalent inhibitors of rhodesain. We demonstrate that the reaction free energy calculated with the PM6/MM potential is in agreement with the experimental data and suggest that the free energy profile for covalent bond formation in a protein environment may be a useful tool for the inhibitor design. (AU)

• Processo FAPESP: 18/21749-3 - Estudo computacional da reação de inibição da enzima cruzaína por inibidores covalentes reversíveis
• Beneficiário: Carlos Alberto Montanari
• Linha de fomento: Auxílio à Pesquisa - Pesquisador Visitante - Brasil
• Processo FAPESP: 13/18009-4 - Planejamento, síntese e atividade tripanossomicida de inibidores covalentes reversíveis da enzima cruzaína
• Beneficiário: Carlos Alberto Montanari
• Linha de fomento: Auxílio à Pesquisa - Temático