Predicting the impact of single-nucleotide polymorphisms in CDK2-flavopiridol complex by molecular dynamics analysis.

Cyclic-dependent kinase 2 (CDK2) is one of the primary protein kinases involved in the regulation of cell cycle progression. Flavopiridol is a flavonoid derived from an indigenous plant act as a potent antitumor drug showing increased inhibitory activity toward CDK2. The presence of deleterious variations in CDK2 may produce different effects in drug-binding adaptability. Studies on nsSNPs of CDK2 gene will provide information on the most likely variants associated with the disease. Furthermore, investigating the relationship between deleterious variants and its ripple effect in the inhibitory action with drug will provide fundamental information for the development of personalized therapies. In this study, we predicted four variants Y15S, V18L, P45L, and V69A of CDK2 as highly deleterious. Occurrence of these variations seriously affected the normal binding capacity of flavopiridol with CDK2. Analysis of 10-ns molecular dynamics (MD) simulation trajectories indicated that the predicted deleterious variants altered the CDK2 stability, flexibility, and surface area. Notably, we noticed the decrease in number of hydrogen bonds between CDK2 and flavopiridol mutant complexes in the whole dynamic period. Overall, this study explores the possible relationship between the CDK2 deleterious variants and the drug-binding ability with the help of molecular docking and MD approaches.