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Combined Ligand and Structure Based Approaches for Narrowing on the Essential Physicochemical Characteristics for CDK4 Inhibition

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journal contribution
posted on 28.07.2008 by Nahren Manuel Mascarenhas, Nanda Ghoshal
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 (q2) as well as an external test set validation (r2pred) 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 R2 substituents to be bulky and polar, while the substituent at R8 to be hydrophobic and comparatively less steric. It also explained why at R6 a variety of substituents are tolerated and how the presence of methyl at R5 enhances binding affinity.