Evaluating the Predictivity of Virtual Screening for Abl Kinase Inhibitors to Hinder Drug Resistance

摘要: Virtual screening methods are now widely used in early stages of drug discovery, aiming to rank potential inhibitors. However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual approaches cannot fully represent all relevant chemical space compounds. In this study, we have taken a retrospective approach evaluate the leukemia target kinase ABL1 and its drug-resistant mutant ABL1-T315I. ‘Dual active’ inhibitors against both targets were grouped together with ligands from different decoy sets tested without explicit use structures (docking). We show how various scoring functions choice influence overall enrichment libraries. Although ligand-based methods, example principal component analyses properties, can distinguish some compounds, addition structural information via docking improves enrichment, consideration multiple conformations (i.e. types I II) achieves best versus ligands, even assuming knowledge binding mode. believe that study be extended other therapeutically important kinases prospective studies.