Assessment of Reversibility for Covalent Cysteine Protease Inhibitors Using Quantum Mechanics/Molecular Mechanics Free Energy Surfaces

Autor(es)

Dos Santos, Alberto M. ; Santana Oliveira, Amanda Ruslana ; da Costa, Clauber H. S. ; Kenny, Peter W. ; Montanari, Carlos A. ; Varela, Jaldyr de Jesus G. ; Lameira, Jeronimo

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 62, n. 17, p. 12-pg., 2022-09-12.

Resumo

We have used molecular dynamics (MD) simulations with hybrid quantum mechanics/molecular mechanics (QM/MM) potentials to investigate the reaction mechanism for covalent inhibition of cathepsin K and assess the reversibility of inhibition. The computed free energy profiles suggest that a nucleophilic attack by the catalytic cysteine on the inhibitor warhead and proton transfer from the catalytic histidine occur in a concerted manner. The results indicate that the reaction is more strongly exergonic for the alkyne-based inhibitors, which bind irreversibly to cathepsin K, than for the nitrile-based inhibitor odanacatib, which binds reversibly. Gas-phase energies were also calculated for the addition of methanethiol to structural prototypes for a number of warheads of interest in cysteine protease inhibitor design in order to assess electrophilicity. The approaches presented in this study are particularly applicable to assessment of novel warheads, and computed transition state geometries can be incorporated into molecular models for covalent docking. (AU)

• Processo FAPESP: 18/21749-3 - Estudo computacional da reação de inibição da enzima cruzaína por inibidores covalentes reversíveis
• Beneficiário: Carlos Alberto Montanari
• Modalidade de apoio: 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
• Modalidade de apoio: Auxílio à Pesquisa - Temático