Unveiling the Structural Insights into the Inhibitor Binding Mechanism of Protein Kinase D1

Authors: Dash R, Arifuzzaman M, Mitra S, Abdul Hannan M, Absar N, Hosen SMZ

Journal: Current Pharmaceutical Design

Description: 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 hinders for the development of selective inhibitors with therapeutic benefits. Thus the study considered the modeling of PKD1 and revealed the ligand binding mechanisms by using extensive molecular modeling approaches. Structural model of PKD1 was created by homology modeling and subsequently, active site identification and ATP binding characterization were accomplished to decipher the structural aspects of PKD1. Furthermore, known inhibitors were docked into the ATP binding site of PKD1 as well as the detailed ligand binding and molecular recognition mechanisms have been investigated by molecular dynamics and binding free energy calculations. The results confessed that, the conserved motifs including G-loop, hinge and catalytic subunits play important role in the ligand binding and selectivity is mediated by the polar interactions with less conserved residues in the hinge region, including Leu662, His663, and Asp665. The computed binding free energies of these inhibitors were in accordance with experimental bioactivity data. Taken together, these mechanistic understanding may help to put forward new hypotheses on new drug design on PKD1, for better therapies to overcome cancer and PKD1 dysregulated disorders.