Dengue virus (DENV) remains a global health challenge, necessitating the identification of novel inhibitors against its NS5 RNA-dependent RNA polymerase (RdRp), a critical enzyme for viral replication. This study evaluates the inhibitory potential of 270 phytochemicals from five local vegetables and computational approaches, with favipiravir as the control. Molecular docking revealed binding energies of -8.8, -8.7, and -8.1 kcal/mol for apigenin-7-glucoside, rutin, and phlorizin, respectively, surpassing favipiravir (-7.4 kcal/mol). These ligands exhibited robust interactions with active site residues, including hydrogen bonds and hydrophobic interactions. Molecular dynamics (MD) simulations over 100 ns confirmed stable protein–ligand complexes, with ligands apigenin-7-glucoside and rutin demonstrating lower Root Mean Square Deviations (RMSD) and favorable Radius of Gyration (Rg) values compared to the control, indicating superior binding stability. Solvent Accessible Surface Area (SASA) and hydrogen bond analyses supported the compactness and interaction strength of apigenin-7-glucoside and rutin. MM/PBSA binding free energy analysis highlighted ligand rutin as the most energetically favorable (-400 to -700 kJ/mol), followed by apigenin-7-glucoside, outperforming favipiravir. Additionally, principal component analysis (PCA) demonstrated distinct ligand-induced conformational effects on NS5 RdRp. The pharmacokinetic evaluations indicated that all three ligands comply with Lipinski’s rule of five, supporting their potential as drug-like candidates. These findings emphasize the potential of vegetable-derived ligands, particularly apigenin-7-glucoside and rutin, as effective inhibitors of DENV NS5 polymerase. Further experimental validation and molecular studies would be required to explore their antiviral applications and potential as alternative therapeutics against dengue.

The present study deals with the advancedin-silicoanalyses of several Apigenin derivatives to explorehuman papillomavirus-associated cervicalcancerand DNA polymerase theta inhibitor propertiesby molecular docking, molecular dynamics, QSAR, drug-likeness, PCA, a dynamic cross-correlation matrix and quantum calculation properties. Initially, the literature study revealed that Apigenin has potent antimicrobial and anticancer properties. So, their potential derivatives are picked up to determinehuman papillomavirus-associated cervicalcancerand DNA polymerase theta inhibitor properties. The findings were streamlined by exposing the in silico molecular docking, highlighting that all the Apigenin derivatives exhibit prospective interactions of energy binding with targeted proteins. The Apigenin 4'-O-Rhamnoside and Apigenin-4'-Alpha-L-Rhamnoside were more potent against HPV45 oncoprotein E7 (PDB ID 2EWL), where the Apigenin and Apigenin 5-O-Beta-D-Glucopyranoside showed significant binding energy against L1 protein of human. Similarly, the binding affinity range is achieved from -7.5 kcal/mol to -8.8 kcal/mol against DNA polymerase theta, representing that Apigenin derivatives should inhibit the DNA polymerase theta (PDB ID 8E23). Then, this finding was confirmed by molecular dynamic simulation at 100ns and analysis of different parameters such as RMSD, RMSF, SASA, H-bond, and RoG profiles and it is found that our selected compounds were found to be potentially stable. When stability testing is passed, the ADMET, pharmacokinetics, and drug-likeness properties are screened and fulfilled by all the criteria. Moreover, QSAR, PCA, Dynamic cross-correlation matrix, and quantum calculation were also conducted and the outcome was satisfied. As this study was carried out usingin silicocomputational approaches and obtained outstanding results. So, to validate these results, further wet-lab experiments might be carried out underin vivoandin vitroconditions.