Combined ligand and structure based approaches for narrowing on the essential physicochemical characteristics for...

In the absence of an experimentally determined 3D structure of CDK4 (Cyclin-Dependent Kinase 4), QSARs (Quantitative Structure Activity Relationship) have been explored to rationalize binding affinity in terms of physicochemical and structural parameters. Further, docking on a homology model of CDK4 validated the derived QSARs and predicted the binding mode of this series of inhibitors. Relevant parameters and leave-one-out (LOO) cross-validation (q (2)) as well as an external test set validation (r (2) pred) judged the statistical significance and predictive ability of the models. Docking enabled a better understanding of protein-ligand interaction and provided a mechanistic interpretation in terms of physicochemical characteristics. It identified a unique hydrogen bonding between the imidazole of His-95 and the pyridine nitrogen in the ligand. It rationalized the need for R 2 substituents to be bulky and polar, while the substituent at R 8 to be hydrophobic and comparatively less steric. It also explained why at R 6 a variety of substituents are tolerated and how the presence of methyl at R 5 enhances binding affinity.