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

Authors :
Sartori GR
Leitão A
Montanari CA
Laughton CA
Source :
PloS one [PLoS One] 2019 Dec 19; Vol. 14 (12), pp. e0222055. Date of Electronic Publication: 2019 Dec 19 (Print Publication: 2019).
Publication Year :
2019

Abstract

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.<br />Competing Interests: The authors have declared that no competing interests exist.

Details

Language :
English
ISSN :
1932-6203
Volume :
14
Issue :
12
Database :
MEDLINE
Journal :
PloS one
Publication Type :
Academic Journal
Accession number :
31856175
Full Text :
https://doi.org/10.1371/journal.pone.0222055