N-(Pyridin-3-yl)pyrimidin-4-amine analogues as potent CDK2 inhibitors: an in silico investigative approach

Cyclin-dependent kinase 2 (CDK2) dysregulation is a significant contributor to the onset of several cancer types. Recently, N-(pyridin-3-yl)pyrimidin-4-amine (NPPA) analogues have been identified as potent candidates for the inhibition of overexpressed CDK2 in cancers. This study examines how the NPPA analogues are endowed with remarkable inhibitory potencies against CDK2. An integrated computational approach is employed by examining the structural properties and reactivities of the NPPA analogues at an electronic level and their molecular interactions with the binding site residues. The effects of inhibitor binding onto the protein structure are dynamically explored and the binding affinities are calculated through a MM/PBSA approach. Our findings reveal that the NPPA analogues hold better chemical reactivity than the reference inhibitor (AZD5438) and are relatively electrophilic in nature. The NPPA analogues establish strong inhibitory interactions within the CDK2 active site and stabilize the protein structure in a well-folded compact state by lowering the fluctuations in the protein structure at the residue level. The binding free energy calculations reveal strong affinities of these inhibitors towards CDK2 inhibition, and the conformational dynamics of the protein structure have unveiled stable protein conformations attained by the inhibitor binding. Out of all the NPPA analogues, NPPA3 has shown remarkable effectiveness as a CDK2 inhibitor. It has favorable chemical properties, forms strong intermolecular interactions with CDK2 active site residues (with a binding affinity of −68.23 kJ mol−1), and achieves improved protein stability through interactions with crucial active site residues. Additionally, it stabilizes the protein in dynamically stable conformations. These findings support the future development of novel CDK2 inhibitors by highlighting some crucial parameters underlying the activity of potent inhibitors.