Chemical function based virtual screening: Discovery of potent lead molecules for the Bcr-Abl tyrosine kinase using VX-680

Abstract

In this work we have present new strategy for designing of pharmacophore and filtering potentially massive combinatorial libraries using structural information of a Ligand- Protein binding interactions. Here we describe the discovery, using Chemical function and shape-based virtual screening, of a potent, ATP site-directed inhibitor of the Bcr-Abl tyrosine kinase, an important and novel drug target for chronic myelogenous leukemia (CML). The chemical feature based pharmacophore model was built for Abl tyrosine kinase from Structure of Abl VX-680 Complex using the View Hypothesis workbench, which is implemented in the Catalyst software. This pharmacophore model consists of five features: two hydrogen bond donors, two hydrogen bond acceptor and one hydrophobic function. This pharmacophore model was used as a query to search NCI, Maybridge and Derwent-WDI2005 databases to identify other new lead compounds. A total of 289 compounds were retrieved as hits from virtual screening.The hits obtained were docked into the active site of Bcr-Abl tyrosine kinase crystal structure (PDB_ID: 2F4J) using GOLD software. Based on the molecular docking we have shown the key interactions between the hit molecules and Abl tyrosine kinase are conserved.