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Unveiling the Structural Insights into the Selective Inhibition of Protein Kinase D1
- Source :
- Current Pharmaceutical Design. 25:1059-1074
- Publication Year :
- 2019
- Publisher :
- Bentham Science Publishers Ltd., 2019.
-
Abstract
- Background:Although protein kinase D1 (PKD1) has been proved to be an efficient target for anticancer drug development, lack of structural details and substrate binding mechanisms are the main obstacles for the development of selective inhibitors with therapeutic benefits.Objective:The present study described the in silico dynamics behaviors of PKD1 in binding with selective and non-selective inhibitors and revealed the critical binding site residues for the selective kinase inhibition.Methods:Here, the three dimensional model of PKD1 was initially constructed by homology modeling along with binding site characterization to explore the non-conserved residues. Subsequently, two known inhibitors were docked to the catalytic site and the detailed ligand binding mechanisms and post binding dyanmics were investigated by molecular dynamics simulation and binding free energy calculations.Results:According to the binding site analysis, PKD1 serves several non-conserved residues in the G-loop, hinge and catalytic subunits. Among them, the residues including Leu662, His663, and Asp665 from hinge region made polar interactions with selective PKD1 inhibitor in docking simulation, which were further validated by the molecular dynamics simulation. Both inhibitors strongly influenced the structural dynamics of PKD1 and their computed binding free energies were in accordance with experimental bioactivity data.Conclusion:The identified non-conserved residues likely to play critical role on molecular reorganization and inhibitor selectivity. Taken together, this study explained the molecular basis of PKD1 specific inhibition, which may help to design new selective inhibitors for better therapies to overcome cancer and PKD1 dysregulated disorders.
- Subjects :
- Pharmacology
0303 health sciences
Binding Sites
Chemistry
In silico
030302 biochemistry & molecular biology
Molecular Dynamics Simulation
Selective inhibition
Molecular Docking Simulation
03 medical and health sciences
Molecular dynamics
Docking (molecular)
Drug Discovery
Biophysics
Protein kinase D1
Homology modeling
Binding site
Hinge region
Protein Kinase Inhibitors
Protein Kinase C
Protein Binding
030304 developmental biology
Subjects
Details
- ISSN :
- 13816128
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Current Pharmaceutical Design
- Accession number :
- edsair.doi.dedup.....fd8e633c00640d1129c7b640c1b720d0
- Full Text :
- https://doi.org/10.2174/1381612825666190527095510