Exploring the Role of Neoflavonoids in Inducing Cell Cycle Arrest in Cancer Cells: In Silico Study

Abstract

Background: Cancer is one of the biggest health issues in the world, and one of the characteristics of oncogenesis is the dysregulation of cell cycle progression. Cyc- lin-dependent kinase 4 (CDK4) is one of the key regulatory factors of G1 to S phase transition, and hence an appealing therapeutic target.

Method: This paper explores the possibility of neoflavonoids as a new CDK4 inhibi- tor using a combined computational method. Our initial study involved a pan-cancer analysis of CDK expression, which was conducted on several databases such as GE- PIA2, TIMER 2.0 and UALCAN, and found that CDK4 was overexpressed in many malignancies, especially glioblastoma, diffuse large B-cell lymphoma and thymoma. Survival analysis also determined that high expression of CDK4 is associated with worse prognosis in a variety of cancer. The CB-Dock2 server with AutoDock Vina was used in molecular docking experiments on 26 neoflavonoid compounds against the ATP-binding site of CDK4.

Results: Our findings have revealed a number of neoflavonoids with binding af- finities similar to those of known CDK4 inhibitors, with 3010628 (-10.8 kcal/mol), 102458506 (-10.5 kcal/mol) and 195328 (-10.4 kcal/mol) coming out as the most promising compounds. The interaction analysis showed in detail that these high- est-ranked neoflavonoids establish important interactions with major residues of the ATP-binding pocket such as hydrogen bonds with Val96 and Asp145, and pi-pi stack- ing with Phe93, which resemble the binding patterns of reference inhibitors.

Conclusion: The results indicate that neoflavonoids are the potential candidates to be further developed as CDK4-targeted anticancer agents, and further experimental efforts should be done to prove their therapeutic potential