Multifaceted computational insights of murrayacinine as dual inhibitors of CDK2 and MAPK3 to combat cervical cancer.

Cervical cancer, the fourth most common cancer among women, and the reported anti-cancer properties of Bergera koenigii prompted this study to explore its therapeutic potential using advanced computational approaches. From a curated library of 394 phytochemicals, a subset of 153 compounds was selected based on initial screening and subsequently evaluated for drug-likeness and ADMET properties. Protein-protein interaction analysis identified 15 key hub genes from 99 drug-disease targets, particularly in pathways related to Human papillomavirus infection. Molecular docking showed that Isomahanine, (+)-Mahanimbicine, and Murrayacinine bound CDK2 and MAPK3 more strongly than Topotecan. All tested compounds had similar affinities for CDK2 (-10.8 to -10.6 kcal/mol) and MAPK3 (-10.8 to -10.5 kcal/mol), while Topotecan showed weaker binding with values of -9.6 kcal/mol for CDK2 and -9.1 kcal/mol for MAPK3. Moreover, Murrayacinine exhibited the most stable binding with CDK2 and MAPK3, showing the lowest RMSD, RMSF, and Rg values, while (+)-Mahanimbicine had the highest fluctuations, and Topotecan showed moderate stability. Additionally, Murrayacinine exhibited the lowest SASA and the highest HBs, confirming its superior binding stability over Topotecan and other phytochemicals, during MD simulation (300 ns) analysis. Protein-ligand distance, pairwise RMSD, and PCA analyses further confirmed the superior structural stability of Murrayacinine. The MM/GBSA analysis confirmed strong interactions between Murrayacinine and target proteins CDK2 and MAPK3 with corresponding binding free energies (-29.6 and -25.1 kcal/mol), compared to Topotecan (-20.9 and -18.1 kcal/mol). Overall, Murrayacinine exhibited higher potency against cervical cancer through its multitargeted action, highlighting B. koenigii phytochemicals as promising drug candidates for treatment.