Identification of Novel AXL Kinase Inhibitors Using Ligand-Based Pharmacophore Screening and Molecular Dynamics Simulations

Abstract

AXL kinase is a promising target in novel drug discovery for cancer. A ligand-based pharmacophore model was generated with the Pharmit web server. Its inbuilt PubChem molecule database was screened and led to 408 candidate molecules. Docking of the AXL kinase active sites with the identified list of candidate molecules was carried out with Autodock Vina docking software. This resulted in four compounds selected for further investigation. Molecular dynamics simulation of two ligands (PubChem-122421875 and PubChem-78160848) showed considerable binding with AXL kinase. From the MM-PBSA binding free energies investigation, the PubChem-122421875 (G = −179.3 kJ/mol) and PubChem-78160848 (G = −208.3 kJ/mol) ligands had favorable protein-ligand complex stability and binding free energy. Hence, PubChem-122421875 and PubChem-78160848 molecules identified in this work could be a potent starting point for developing novel AXL kinase inhibitor molecules.