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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.

SUBMITTER: Baig MH

PROVIDER: S-EPMC9204300 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Baig Mohammad Hassan MH Yousuf Mohd M Khan Mohd Imran MI Khan Imran I Ahmad Irfan I Alshahrani Mohammad Y MY Hassan Md Imtaiyaz MI Dong Jae-June JJ

Frontiers in oncology 20220526

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 dynamic ...[more]

PMID: 35720007

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Project description:BackgroundPsidium guajava L., Myrtaceae, is used widely in traditional medicine for the treatment of diarrhoea, dysentery, gastroenteritis, stomachaches, and indigestion. However, the effect of the leaf extract of P. guajava on the pathogenesis of infectious diarrhoea has not been studied. The present study evaluates the effect of a hot aqueous extract (decoction) of dried leaves of P. guajava on parameters associated with pathogenicity of infectious diarrhoea. The aim was to understand its possible mechanism(s) of action in controlling infectious diarrhoea and compare it with quercetin, one of the most reported active constituents of P. guajava with antidiarrhoeal activity.MethodsThe crude decoction and quercetin were studied for their antibacterial activity and effect on virulence features of common diarrhoeal pathogens viz. colonization of epithelial cells and production and action of enterotoxins. Colonization as measured by adherence of enteropathogenic Escherichia coli (EPEC) and invasion of enteroinvasive E. coli (EIEC) and Shigella flexneri was assessed using HEp-2 cell line. The production of E. coli heat labile toxin (LT) and cholera toxin (CT) and their binding to ganglioside monosialic acid (GM1) were studied by GM1-ELISA whereas the production and action of E. coli heat stable toxin (ST) was assessed by suckling mouse assay.ResultsThe decoction of P. guajava showed antibacterial activity towards S. flexneri and Vibrio cholerae. It decreased production of both LT and CT and their binding to GM1. However, it had no effect on production and action of ST. The decoction also inhibited the adherence of EPEC and invasion by both EIEC and S. flexneri to HEp-2 cells. Quercetin, on the other hand, had no antibacterial activity at the concentrations used nor did it affect any of the enterotoxins. Although it did not affect adherence of EPEC, it inhibited the invasion of both EIEC and S. flexneri to HEp-2 cells.ConclusionCollectively, the results indicate that the decoction of P. guajava leaves is an effective antidiarrhoeal agent and that the entire spectrum of its antidiarrhoeal activity is not due to quercetin alone.

Project description:Evidence that elongation factor 2 kinase (eEF-2K) has potential as a target for anticancer therapy and possibly for the treatment of depression is emerging. Here the steady-state kinetic mechanism of eEF-2K is presented using a peptide substrate and is shown to conform to an ordered sequential mechanism with ATP binding first. Substrate inhibition by the peptide was observed and revealed to be competitive with ATP, explaining the observed ordered mechanism. Several small molecules are reported to inhibit eEF-2K activity with the most notable being the histidine kinase inhibitor NH125, which has been used in a number of studies to characterize eEF-2K activity in cells. While NH125 was previously reported to inhibit eEF-2K in vitro with an IC(50) of 60 nM, its mechanism of action was not established. Using the same kinetic assay, the ability of an authentic sample of NH125 to inhibit eEF-2K was assessed over a range of substrate and inhibitor concentrations. A typical dose-response curve for the inhibition of eEF-2K by NH125 is best fit to an IC(50) of 18 ± 0.25 ?M and a Hill coefficient of 3.7 ± 0.14, suggesting that NH125 is a weak inhibitor of eEF-2K under the experimental conditions of a standard in vitro kinase assay. To test the possibility that NH125 is a potent inhibitor of eEF2 phosphorylation, we assessed its ability to inhibit the phosphorylation of eEF2. Under standard kinase assay conditions, NH125 exhibits a similar weak ability to inhibit the phosphorylation of eEF2 by eEF-2K. Notably, the activity of NH125 is severely abrogated by the addition of 0.1% Triton to the kinase assay through a process that can be reversed upon dilution. These studies suggest that NH125 is a nonspecific colloidal aggregator in vitro, a notion further supported by the observation that NH125 inhibits other protein kinases, such as ERK2 and TRPM7 in a manner similar to that of eEF-2K. As NH125 is reported to inhibit eEF-2K in a cellular environment, its ability to inhibit eEF2 phosphorylation was assessed in MDA-MB-231 breast cancer, A549 lung cancer, and HEK-293T cell lines using a Western blot approach. No sign of a decrease in the level of eEF2 phosphorylation was observed up to 12 h following addition of NH125 to the media. Furthermore, contrary to the previously reported literatures, NH125 induced the phosphorylation of eEF-2.

Dataset Information

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

Publications

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

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