Why pyridine containing pyrido[2,3-d]pyrimidin-7-ones selectively inhibit CDK4 than CDK2: Insights from molecular dynamics simulation

Designing selective cyclin-dependent kinase 4 (CDK4) inhibitors is an area of intense research to develop potential anticancer drugs. The molecular basis governing the selective inhibition of CDK4 by lig17 (6-bromo-8-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one) has been investigated using molecular dynamics simulation. The positive charge on the ligand was determined to be an important contributor for CDK4 selectivity due to the electronegative nature of its active site. Similar studies on CDK2 indicated that Lys89 intrudes into the active site displacing the positive charge on lig17 away from the active center. This intrusion was observed to propel a drastic conformational change in lig17, weakening its binding interactions with the protein. The pyridine nitrogen (NAR) of lig17 was capable of interacting with His95 (CDK4) through hydrogen bonding. NAR also showed a strong tendency to mediate protein–ligand interactions through a bridged water molecule, only when bound to CDK4. The G-loop of CDK4 was observed to fluctuate extensively when complexed with lig17 and a novel “flipping-out” mechanism exhibited by Tyr17CDK4/CDK4–17 is reported in this study. Although these proteins have similar folds, the results from principal component analysis (PCA) indicate that CDK4 and CDK2 follow an anti-correlated behavior towards the accessibility of the active site.