Desmodin and isopongachromene as potential inhibitors of cyclin-dependent kinase 5: phytoconstituents targeting anticancer and neurological therapy

Abstract

Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine–threonine protein kinase vital for neuronal cell cycle arrest and differentiation. It activates by binding with p35 and p39 and is important for the functioning of the nervous system. A growing body of evidence suggests that CDK5 contributes to the onset and progression of neurodegeneration and tumorigenesis and represents itself as a potential therapeutic target. Our research illustrates virtual screening of phytochemicals from the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) library to search for potential inhibitors of CDK5. Initially, the compounds from the parent library were filtered out via their physicochemical properties following the Lipinski rule of five. Then sequentially, molecular docking-based virtual screening, PAINS filter, ADMET, PASS analysis, and molecular dynamics (MD) simulation were done using various computational tools to rule out adversities that can cause hindrances in the identification of potential inhibitors of CDK5. Finally, two compounds were selected via the extensive screening showing significant binding with CDK5 ATP-binding pocket and ultimately were selected as potent ATP-competitive inhibitors of CDK5. Finally, we propose that the elucidated compounds Desmodin and Isopongachromene can be used further in the drug discovery process and act as therapeutics in the medical industry to treat certain complex diseases, including cancer and neurodegeneration.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cyclin-dependent kinase 5
• desmodin
• isopongachromene
• MD simulation
• small molecule inhibitors
• virtual screening

Disclosure statement

There is no conflict of interest to declare.

Authors’ contributions

A.A., T.M., and S.B. contributed to conceptualization; A.A., T.M., S.E.S., and F.A.A. contributed to methodology; W.A.A. and G.M.A. contributed to software; T.M. and S.S.B. contributed to validation; A.A., S.S.B., A.M.E., F.A.A., and W.A.A. contributed to formal analysis. T.M. and N.M.A. contributed to investigation; A.A., F.A.A., and M.S. contributed to resources; A.A. and T.M. contributed to data curation; T.M. and A.M.E. contributed to writing—original draft preparation; A.A., G.M.A. and N.M.A. contributed to writing—review and editing; T.M. contributed to visualization; A.A. and S.S.B. involved in supervision; A.A. and T.M. involved in project administration; A.A and M.S. contributed to funding acquisition. All authors have read and agreed to the current version of the manuscript.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University, Saudi Arabia, for funding this work through the Large Research Groups Program under grant number RGP.2/137/1443. This work was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, Saudi Arabia under grant no. (KEP-4-140-42). The authors, therefore, acknowledge with thanks DSR technical and financial support. The authors are also grateful to Ajman University for funding this work through 2021-IRG-PH-06. Nasser M Alorfi would like to thank the ‎Deanship of Scientific Research at Umm Al-Qura University ‎for supporting this work by grant code (22UQU4420038DSR02).