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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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]
Total Authors: 6
Affiliation:
[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
Total Affiliations: 2
Document type: Journal article
Source: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 60, n. 2, p. 880-889, FEB 2020.
Web of Science Citations: 1
Abstract

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)

FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 18/21749-3 - Computational study of cruzain enzyme by reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support Opportunities: Research Grants - Visiting Researcher Grant - Brazil