Back to Search
Start Over
Molecular Modeling Study for Inhibition Mechanism of Human Chymase and Its Application in Inhibitor Design
- Source :
- PLoS ONE, PLoS ONE, Vol 8, Iss 4, p e62740 (2013), PLOS ONE(8): 4
- Publication Year :
- 2013
- Publisher :
- Public Library of Science, 2013.
-
Abstract
- Human chymase catalyzes the hydrolysis of peptide bonds. Three chymase inhibitors with very similar chemical structures but highly different inhibitory profiles towards the hydrolase function of chymase were selected with the aim of elucidating the origin of disparities in their biological activities. As a substrate (angiotensin-I) bound crystal structure is not available, molecular docking was performed to dock the substrate into the active site. Molecular dynamics simulations of chymase complexes with inhibitors and substrate were performed to calculate the binding orientation of inhibitors and substrate as well as to characterize conformational changes in the active site. The results elucidate details of the 3D chymase structure as well as the importance of K40 in hydrolase function. Binding mode analysis showed that substitution of a heavier Cl atom at the phenyl ring of most active inhibitor produced a great deal of variation in its orientation causing the phosphinate group to interact strongly with residue K40. Dynamics simulations revealed the conformational variation in region of V36-F41 upon substrate and inhibitor binding induced a shift in the location of K40 thus changing its interactions with them. Chymase complexes with the most active compound and substrate were used for development of a hybrid pharmacophore model which was applied in databases screening. Finally, hits which bound well at the active site, exhibited key interactions and favorable electronic properties were identified as possible inhibitors for chymase. This study not only elucidates inhibitory mechanism of chymase inhibitors but also provides key structural insights which will aid in the rational design of novel potent inhibitors of the enzyme. In general, the strategy applied in the current study could be a promising computational approach and may be generally applicable to drug design for other enzymes.
- Subjects :
- Models, Molecular
Molecular model
Stereochemistry
Hydrolases
Protein Conformation
Biophysics
Drug Evaluation, Preclinical
lcsh:Medicine
Molecular Dynamics
Ligands
Biochemistry
Biophysics Simulations
Protein structure
Computational Chemistry
Chymases
Hydrolase
Drug Discovery
Biochemical Simulations
Humans
Biomacromolecule-Ligand Interactions
Enzyme Inhibitors
lcsh:Science
Biochemistry Simulations
Biology
Multidisciplinary
biology
Chemistry
Enzyme Classes
lcsh:R
Chymase
Rational design
Active site
Substrate (chemistry)
Computational Biology
Enzymes
Molecular Docking Simulation
Small Molecules
Drug Design
biology.protein
lcsh:Q
Biophysic Al Simulations
Pharmacophore
Medicinal Chemistry
Research Article
Biotechnology
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 8
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....a1a2f6bb5b0052403c284d29f8e20ddc