In silico design, modelling and molecular mechanisms of Axl receptor tyrosine kinase inhibitors.

Abstract

A kinase domain from receptor tyrosine kinases (RTKs) regulate intracellular communications to control cellular metabolic activities. Some of the malignant cells have upregulated and overexpressed RTKs which are responsible for angiogenesis in many metastatic cancers. Axl RTK is present in most of the eukaryotic cells and all metastatic cancer cells have overexpressed Axl tyrosine kinase to trigger uncontrolled growth and angiogenesis in the malignant cells. The upregulated kinases can be inhibited in its active and inactive states in the presence of small organic molecule inhibitors. Kinase inhibitors have been discovered to arrest the signal transduction pathways in the malignant cells as a therapy and cure for cancer. In this work, small molecule databases were screened using the pharmacophore features of a macrocyclic inhibitor (7YS) taken as reference from the crystal structure of Axl kinase domain. Pharmacophore based virtual screening of small molecule libraries (CHEMBL32, ChemDiv, Chemspace, Mcule, MolProt, PubChem and Zinc), followed by molecular docking, molecular dynamics simulations, binding energies from MM-PBSA calculations and trajectory analysis as principal component analysis were studied. The molecular basis for the binding of macrocyclic inhibitor, ATP and seven screened hit molecules bound at Axl kinase domain in two different modes at catalytic and regulatory sites was analyzed.