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

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.

SUBMITTER: Sartori GR

PROVIDER: S-EPMC6922342 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Sartori Geraldo Rodrigues GR Leitão Andrei A Montanari Carlos A CA Laughton Charles A CA

PloS one 20191219 12

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 ...[more]

PMID: 31856175

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