Identification of selective cyclin-dependent kinase 2 inhibitor from the library of pyrrolone-fused benzosuberene compounds: an in silico exploration

Abstract

The over-expression of cyclin-dependent kinase 2 is related to multiple cancers, which has led them to be a widely researched topic for nearly two decades. The prime focus of the present research is to design new potent and specific inhibitors against CDK2 to suppress cancer cell proliferation. In this study, we have chosen Flavopiridol, SU9516, and CVT-313 as standard inhibitors to compare with in-house synthesized pyrrolone-fused benzosuberene (PBS) compounds. We scrutinized Ligand2 as a selective inhibitor of CDK2 without off-target binding (CDK1 and CDK9) based on ligand efficiency and binding affinity. Interpretation of dynamic simulations and binding free energy studies unveiled that Ligand2 has a stable and equivalent free energy to standard inhibitors. These outcomes led towards positioning a potential natural molecule as selective inhibitor for CDK2 with low side effects.

Communicated by Ramaswamy H. Sarma

Keywords:

• Flavopiridol
• SU9516
• PBS compounds
• CVT-313
• CDK2
• MM-PBSA

Acknowledgements

We gratefully acknowledge the CSIR-Institute of Himalayan Bioresource Technology, Palampur for providing the facilities to carry out this work. This manuscript represents CSIR-IHBT communication no 4779.

Author contributions

RP conceived of and designed the study. RP, RS, VKB, JS analyzed and interpreted the data. PD provided chemical molecules for computational studies. RS, VKB, JS, PD, and RP critically revised it for important intellectual content. All authors gave final approval of the version to be published.

Competing interests statement

All authors hereby declare that they have no competing interests related to this work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Board of Research in Nuclear Sciences, Department of Atomic Energy, Mumbai, India vide letter No: 37(1)/14/26/2015/BRNS, the Department of Science and Technology, New Delhi, India SERB File No: ECR/2016/000031.