FlexE ensemble docking approach to virtual screening for CDK2 inhibitors

Abstract

In spite of a proven potential and effectiveness of FlexE in docking flexible ligands into an ensemble of protein structures, FlexE has rarely been successful in virtual screening situations. In this study, we constructed cyclin-dependent kinase 2 (CDK2) ensemble structures which have exactly the same backbone conformations as 1AQ1 but differ only at the side chain torsion angles of the key amino acid (Lys33, Phe80, Lys89 and Asp145) residues: the torsion angles observed in the 17 CDK2 crystal structures were adapted to represent conformational flexibility. FlexE ensemble docking protocol then completely samples the full conformational fields generated by combination of torsions of the four amino acids in the ATP binding site. Virtual screening for CDK2 inhibitors by using the FlexE ensemble docking of a database composed of 48,703 inactives and 82 actives showed significant enrichment factor (EF = 18.5), and successfully identified 71 actives among the top 132 ligands (53.8%) ranked by total energy scores. Moreover, total energy scoring followed by visual inspection filtered-off non-specific binders among the highly-ranked ligands to increase the ratio of actives-to-inactives to 71:13 at the top 5% of the virtual screening solutions.