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Ligand-induced conformational selection predicts the selectivity of cysteine protease inhibitors.
- Source :
-
PloS one [PLoS One] 2019 Dec 19; Vol. 14 (12), pp. e0222055. Date of Electronic Publication: 2019 Dec 19 (Print Publication: 2019). - Publication Year :
- 2019
-
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.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Animals
Catalytic Domain
Cathepsin L metabolism
Cathepsins antagonists & inhibitors
Cathepsins metabolism
Chagas Disease
Cysteine Endopeptidases metabolism
Cysteine Proteases metabolism
Humans
Ligands
Molecular Dynamics Simulation
Principal Component Analysis methods
Protein Binding
Protozoan Proteins metabolism
Structure-Activity Relationship
Trypanosoma cruzi metabolism
Cysteine Proteinase Inhibitors metabolism
Cysteine Proteinase Inhibitors pharmacology
Protozoan Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 14
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 31856175
- Full Text :
- https://doi.org/10.1371/journal.pone.0222055