Exploring therapeutic potential of Rutin by investigating its cyclin-dependent kinase 6 inhibitory activity and binding affinity

Abstract

Cyclin-dependent kinase 6 (CDK6) participates in numerous signalling pathways and regulates various physiological processes. Due to its unique structural features and promising therapeutic potential, CDK6 has emerged as a drug target for designing and developing small-molecule inhibitors for anti-cancer therapeutics and other CDK6-associated diseases. The current study evaluates binding affinity and the inhibitory potential of rutin for CDK6 to develop a proof of concept for rutin as a potent CDK6 inhibitor. Molecular docking and 200 ns all-atom simulations reveal that rutin binds to the active site pocket of CDK6, forming interactions with key residues of the binding pocket. In addition, the CDK6-rutin complex remains stable throughout the simulation trajectory. A high binding constant (Ka = 7.6 × 10⁵M^-1) indicates that rutin has a strong affinity for CDK6. Isothermal titration calorimetry has further validated a strong binding of rutin with CDK6 and its spontaneous nature. The kinase activity of CDK6 is significantly inhibited by rutin with an IC₅₀ value of 3.10 μM. Our findings highlight the significant role of rutin in developing potential therapeutic molecules to manage cancer and CDK6-associated diseases via therapeutic targeting of CDK6.

Keywords: Anti-cancer therapy; Cyclin-dependent kinase 6; Drug design and development; Kinase inhibitor; Molecular dynamics simulation; Natural compounds.