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Unveiling the Structural Insights into the Selective Inhibition of Protein Kinase D1

Authors :
S. M. Zahid Hosen
Abdul Hannan
Sarmistha Mitra
Raju Dash
Nurul Absar
Arifuzzaman
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.

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