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.