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

Author(s)

Sartori, Geraldo Rodrigues ^[1] ; Leitao, Andrei ^[1] ; Montanari, Carlos A. ^[1] ; Laughton, Charles A. ^{[2, 3]}

Affiliation

^[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

• Document type: Journal article
• Source: PLoS One; v. 14, n. 12 DEC 19 2019.
• Web of Science Citations: 1

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. (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