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

Author

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  • Geraldo Rodrigues Sartori
  • Andrei Leitão
  • Carlos A Montanari
  • Charles A Laughton

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.

Suggested Citation

  • Geraldo Rodrigues Sartori & Andrei Leitão & Carlos A Montanari & Charles A Laughton, 2019. "Ligand-induced conformational selection predicts the selectivity of cysteine protease inhibitors," PLOS ONE, Public Library of Science, vol. 14(12), pages 1-16, December.
    • Handle: RePEc:plo:pone00:0222055
    DOI: 10.1371/journal.pone.0222055
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