Ligand-induced conformational selection predicts the selectivity of cysteine protease inhibitors.
Animals
Catalytic Domain
Cathepsin L
/ metabolism
Cathepsins
/ antagonists & inhibitors
Chagas Disease
Cysteine Endopeptidases
/ metabolism
Cysteine Proteases
/ metabolism
Cysteine Proteinase Inhibitors
/ metabolism
Humans
Ligands
Molecular Dynamics Simulation
Principal Component Analysis
/ methods
Protein Binding
Protozoan Proteins
/ antagonists & inhibitors
Structure-Activity Relationship
Trypanosoma cruzi
/ metabolism
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
15
08
2019
accepted:
19
11
2019
entrez:
20
12
2019
pubmed:
20
12
2019
medline:
21
3
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31856175
doi: 10.1371/journal.pone.0222055
pii: PONE-D-19-23070
pmc: PMC6922342
doi:
Substances chimiques
Cysteine Proteinase Inhibitors
0
Ligands
0
Protozoan Proteins
0
Cathepsins
EC 3.4.-
Cysteine Proteases
EC 3.4.-
Cysteine Endopeptidases
EC 3.4.22.-
Cathepsin L
EC 3.4.22.15
cruzipain
EC 3.4.22.51
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0222055Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/L01386X/1
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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