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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.)

Ligand-induced conformational selection predicts the selectivity of cysteine protease inhibitors

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Sartori, Geraldo Rodrigues [1] ; Leitao, Andrei [1] ; Montanari, Carlos A. [1] ; Laughton, Charles A. [2, 3]
Total Authors: 4
[1] Univ Sao Paulo, Grp Quim Med IQSC USP, Inst Quim Sao Carlos, Sao Carlos, SP - Brazil
[2] Univ Nottingham, Sch Pharm, Nottingham - England
[3] Univ Nottingham, Ctr Biomol Sci, Nottingham - England
Total Affiliations: 3
Document type: Journal article
Source: PLoS One; v. 14, n. 12 DEC 19 2019.
Web of Science Citations: 1

Cruzain, a cysteine protease of Trypanosoma cruzi, is a validated target for the treatment of Chagas disease. Due to its high similarity in three-dimensional structure with human cathepsins and their sequence identity above 70% in the active site regions, identifying potent but selective cruzain inhibitors with low side effects on the host organism represents a significant challenge. Here a panel of nitrile ligands with varying potencies against cathepsin K, cathepsin L and cruzain, are studied by molecular dynamics simulations as both non-covalent and covalent complexes. Principal component analysis (PCA), identifies and quantifies patterns of ligand-induced conformational selection that enable the construction of a decision tree which can predict with high confidence a low-nanomolar inhibitor of each of three proteins, and determine the selectivity for one against others. (AU)

FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support type: Research Projects - Thematic Grants