Predicting binding energies of CDK6 inhibitors in the hit-to-lead process

The main challenge for the ??hit-to-lead?? stage in the drug discovery process relies on the accuracy of existing docking methods. In fact, accuracy of docking methods depends not only on the scoring function used to rank the poses but also on the ability of the docking method to reproduce the experimental binding mode. At this purpose, the performance of different approximations to properly dock and score compounds with known activity in a narrow range of IC₅₀ values was analyzed. A set of five ATP-competitive CDK6 inhibitors and three receptor conformations for CDK6 were considered for analysis, and three methodologies were used and analyzed in order to include different degrees of receptor flexibility. Thus, a completely rigid receptor is considered when using Glide, while the so-called Induced Fit Docking Protocol accounts for receptor sidechain rearrangements. Finally, force field calculations were also performed in order to consider a completely flexible receptor.