A virtual screening investigation to identify bioactive natural compounds as potential inhibitors of cyclin-dependent kinase 9

Abstract

Cyclin-dependent kinase 9 (CDK9) is a transcription-associated protein involved in controlling the cell cycle and is often deregulated in stress conditions. CDK9 is being studied as a well-known druggable target for developing effective therapeutics against a wide range of cancer, cardiac dysfunction and inflammatory diseases. Owing to the significance of CDK9 in the etiology of hematological and solid malignancies, its structure, biological activity, regulation and its pharmacological inhibition are being explored for therapeutic management of cancer. We employed a structure-based virtual high-throughput screening of bioactive compounds from the IMPPAT database to discover potential bioactive inhibitors of CDK9. The preliminary results were obtained from the Lipinski criteria, ADMET parameters and sorting compounds without any PAINS patterns. Subsequently, binding affinity and selectivity analyses were used to find effective CDK9 hits. This screening resulted in the identification of two natural compounds, Glabrene and Guggulsterone with high affinity and specificity for the CDK9 binding site. Both compounds exhibit drug-like characteristics, as projected by ADMET analysis, physicochemical data and PASS evaluation. Both compounds preferentially bind to the ATP-binding pocket of CDK9 and interact with functionally important residues. Further, the dynamics and consistency of CDK9 interaction with Glabrene and Guggulsteron were evaluated through all-atom molecular dynamic (MD) simulations which suggested the stability of both complexes. The results might be deployed to introduce novel CDK9 inhibitors that may treat life-threatening diseases, including cancer.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cyclin-dependent kinase 9
• natural compounds
• drug discovery
• virtual high-throughput screening
• MD simulation

Authors’ contributions

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

Disclosure statement

There is no conflict of interest to declare.

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 thankful to Ajman University, United Arab Emirates for providing all the necessary facilities.