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

Autoři: Geraldo Rodrigues Sartori aff001;  Andrei Leitão aff001;  Carlos A. Montanari aff001;  Charles A. Laughton aff002
Působiště autorů: Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil aff001;  School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, Nottingham, England, United Kingdom aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222055


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.

Klíčová slova:

Biochemical simulations – Cysteine – Decision trees – Molecular dynamics – principal component analysis – Sulfur – Nitriles – Cysteine proteases


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