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bioRxiv · 10.1101/744953

Ligand-induced Conformational Selection Predicts the Selectivity of Cysteine Protease Inhibitors

Sartori, G. R.·Leitao, A.·Montanari, C.·Laughton, C. A.
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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.

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Sartori, G. R., Leitao, A., Montanari, C., Laughton, C. A.. 2019-08-22. Ligand-induced Conformational Selection Predicts the Selectivity of Cysteine Protease Inhibitors. https://doi.org/10.1101/744953

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