Docking-based development of purine-like inhibitors of cyclin-dependent kinase-2

The cell division cycle is controlled by cyclin-dependent kinases (cdk), wh ich consist of a catalytic subunit (cdk1-cdk8) and a regulatory subunit (cy clin A-H). Purine-like inhibitors of cyclin-dependent kinases have recently been found to be of potential use as anticancer drugs. Rigid and flexible docking techniques were used for analysis of binding mode and design of new inhibitors. X-ray structures of three (ATP, olomoucine, roscovitine) cdk2 complexes were available at the beginning of the study and were used to opt imize the docking parameters. The new potential inhibitors were then docked into the cdk2 enzyme, and the enzyme/inhibitor interaction energies were c alculated and tested against the assayed activities of cdk1 (37 compounds) and cdk2 (9 compounds). A significant rank correlation between the activity and the rigid docking interaction energy has been found. This implies that (i) the rigid docking can be used as a tool for qualitative prediction of activity and (ii) values obtained by the rigid docking technique into the c dk2 active site can also be used for the prediction of cdk1 activity. While the resulting geometries obtained by the rigid docking are in good agreeme nt with the X-ray data, the flexible docking did not always produce the sam e inhibitor conformation as that found in the crystal.