Investigating the common pharmacophoric points of PDK1 inhibitors as anti-cancer agents using an alignment independent 3D-QSAR, molecular docking and molecular dynamic simulation

Abstract

The glycolytic enzyme 3-Phosphoinositide-dependent protein kinase-1 (PDK1), a member of the serine/threonine kinase family, is a promising target for developing novel anticancer drugs due to its vital role in growth and survival of cancer cells and tumor angiogenesis. A MIF base alignment independent, Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) study was conducted to highlight the correlation between PDK1 inhibitors and their structural characteristics, thus indicating the most effective molecular properties of the inhibitors as anticancer agents. Using the Kennard-Stone algorithm to separate calibration and validation subsets, Partial Least-Square (PLS) method application shows excellent agreement between experimental and predicted values (R2=0.85, Q2LOO=0.77 and R2Perd=0.93), making it a reliable model for future drug design approaches. In addition, the active site of the PDK1 receptor protein was examined via Molecular Docking with both passive and active compounds. In order to study the effect of inhibitors on PDK1 structure, 10 ns Molecular Dynamics (MD) simulation of free protein and protein-ligand complex was performed and compared. Comparing the 3D-QSAR, docking and molecular simulation outcomes, the prevailing pharmacophoric use of PDK1 inhibitors as anti-cancer agents have been highlighted. The comprehensive information of this approach reveals important structural variables and their relationship with PDK1 inhibitory activity and PDK1 cavity residues which could be valuable for designing anticancer candidates.