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

Authors
 Mohammad Hassan Baig  ;  Mohd Yousuf  ;  Mohd Imran Khan  ;  Imran Khan  ;  Irfan Ahmad  ;  Mohammad Y Alshahrani  ;  Md Imtaiyaz Hassan  ;  Jae-June Dong 
Citation
 FRONTIERS IN ONCOLOGY, Vol.12 : 865454, 2022-05 
Journal Title
FRONTIERS IN ONCOLOGY
Issue Date
2022-05
Keywords
MD simulation ; anticancer therapy ; cyclin-dependent kinases ; drug design and development ; drug repurposing ; molecular docking
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.
Files in This Item:
T202202064.pdf Download
DOI
10.3389/fonc.2022.865454
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Family Medicine (가정의학교실) > 1. Journal Papers
Yonsei Authors
Dong, Jae June(동재준) ORCID logo https://orcid.org/0000-0002-2420-2155
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/188622
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