Investigating the Mechanism of Inhibition of Cyclin-Dependent Kinase 6 Inhibitory Potential by Selonsertib: Newer Insights Into Drug Repurposing

Abstract

Cyclin-dependent kinases (CDKs) play significant roles in numerous physiological, and are considered an attractive drug target for cancer, neurodegenerative, and inflammatory diseases. In the present study, we have aimed to investigate the binding affinity and inhibitory potential of selonsertib toward CDK6. Using the drug repurposing approach, we performed molecular docking of selonsertib with CDK6 and observed a significant binding affinity. To ascertain, we further performed essential dynamics analysis and free energy calculation, which suggested the formation of a stable selonsertib-CDK6 complex. The in-silico findings were further experimentally validated. The recombinant CDK6 was expressed, purified, and treated with selonsertib. The binding affinity of selonsertib to CDK6 was estimated by fluorescence binding studies and enzyme inhibition assay. The results indicated an appreciable binding of selonsertib against CDK6, which subsequently inhibits its activity with a commendable IC50 value (9.8 μM). We concluded that targeting CDK6 by selonsertib can be an efficient therapeutic approach to cancer and other CDK6-related diseases. These observations provide a promising opportunity to utilize selonsertib to address CDK6-related human pathologies.

A comprehensive analysis of the role of molecular docking in the development of anticancer agents against the cell cycle CDK enzyme

“…The result of fluorescence binding studies and enzyme inhibition assay indicated an acceptable binding with an IC 50 value of 9.8 µM. Thus, by in silico analysis, fluorescence studies, and enzyme inhibition assay, they represented molecule 113 as a promising candidate against cancer (Baig et al, 2022). Yousuf et al (2022) identified taurine (114) (Fig.…”

“…They predicted that this could be the reason behind the poorer CDK6 inhibitory activity of 112 in comparison to palbociclib (Huang et al, 2022). Baig et al (2022) proposed that selonserin (113) (Fig. 24) can be used as a potent inhibitor of CDK6.…”