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

Sartori, Geraldo Rodrigues; Leit�o, Andrei; Montanari, Carlos A.; Laughton, Charles A.

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.

• Journal Article Type: Article
• Acceptance Date: Dec 6, 2019
• Online Publication Date: Dec 19, 2019
• Publication Date: Dec 19, 2019
• Deposit Date: Jul 20, 2020
• Publicly Available Date: Jul 20, 2020
• Journal: PLOS ONE
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Issue: 12
• Article Number: e0222055
• DOI: https://doi.org/10.1371/journal.pone.0222055
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Agricultural and Biological Sciences; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/3611789
• Publisher URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222055