Novel computational and drug design strategies for inhibition of human papillomavirus-associated cervical cancer and DNA polymerase theta receptor by Apigenin derivatives

Abstract

The present study deals with the advanced in-silico analyses of several Apigenin derivatives to explore human papillomavirus-associated cervical cancer and DNA polymerase theta inhibitor properties by molecular docking, molecular dynamics, QSAR, drug-likeness, PCA, a dynamic cross-correlation matrix and quantum calculation properties. The initial literature study revealed the potent antimicrobial and anticancer properties of Apigenin, prompting the selection of its potential derivatives to investigate their abilities as inhibitors of human papillomavirus-associated cervical cancer and DNA polymerase theta. In silico molecular docking was employed to streamline the findings, revealing promising energy-binding interactions between all Apigenin derivatives and the targeted proteins. Notably, Apigenin 4'-O-Rhamnoside and Apigenin-4'-Alpha-L-Rhamnoside demonstrated higher potency against the HPV45 oncoprotein E7 (PDB ID 2EWL), while Apigenin and Apigenin 5-O-Beta-D-Glucopyranoside exhibited significant binding energy against the L1 protein in humans. Similarly, a binding affinity range of - 7.5 kcal/mol to - 8.8 kcal/mol was achieved against DNA polymerase theta, indicating the potential of Apigenin derivatives to inhibit this enzyme (PDB ID 8E23). This finding was further validated through molecular dynamic simulation for 100 ns, analyzing parameters such as RMSD, RMSF, SASA, H-bond, and RoG profiles. The results demonstrated the stability of the selected compounds during the simulation. After passing the stability testing, the compounds underwent screening for ADMET, pharmacokinetics, and drug-likeness properties, fulfilling all the necessary criteria. QSAR, PCA, dynamic cross-correlation matrix, and quantum calculations were conducted, yielding satisfactory outcomes. Since this study utilized in silico computational approaches and obtained outstanding results, further validation is crucial. Therefore, additional wet-lab experiments should be conducted under in vivo and in vitro conditions to confirm the findings.

Figure 1

Chemical structures of studied compounds.

Figure 2

Three-dimensional protein structure of the targeted receptor.

Figure 3

Docking interactions between the proposed compound.

Figure 4

RMSD analysis of Apo and the ligand complex (C-Alpha) in molecular dynamics simulations for the time scale of 100 ns. The black and red colors represented the Apigenin, rand Apigenin-5-O-beta-d glucopyranoside complexes with L1 protein of human papillomavirus (PDB ID 6L31) the green is represented the Apo protein (PDB ID 6L31).

Figure 5

RMSD histograms show (A) Apigenin, (B) Apigenin-5-O-beta-d glucopyranoside, and (C) Apo protein.

Figure 6

Displays the amino acid positional variation using RMSF analysis of Apo and ligand complexes in 100 ns molecular dynamics simulations.

Figure 7

Represents the ROG values of the Apo-protein and protein–ligand complexes to the protein backbone for 100 ns. RoG of Apigenin-6L31, Apigenin-5-O-beta-D glucopyranoside -6L31, and Apo_6L31 are shown in black, red, and green respectively.

Figure 8

SASA analysis for the native structure of Apo_6L31 (black) and its complex with Apigenin (red) and Apigenin-5-O-beta-D glucopyranoside (green).

Figure 9

Represents the number of hydrogen bonds responsible for the stability of the complexes (Apigenin-6L31 and Apigenin-5-6L31) throughout the 100 ns.

Figure 10

Contact frequency analysis during the MD simulation. A contact frequency plot of 6L31 residues interacting with Apigenin (black) and Apigenin-5-O-beta-d glucopyranoside antigen (red).

Figure 11

Principal component analysis of (a) Apigenin, (b) Apigenin-5, and (c) Apo protein. Each point represents the protein’s conformation on the X and Y axes. The chromatic distribution of blue and red dots was utilized to depict the extent of conformational alterations in the simulation. The color gradient ranging from blue to white to red was indicative of the duration of the simulation. The color blue designates the initial timestep, while the color white represents the intermediate timestep, and the color red signifies the final timestep.

Figure 12

Ca-residue cross-correlation profiles for (A) Apigenin, (B) Apigenin-5-O-beta-D glucopyranoside proteins, and (C) Apo protein [L1 protein of human papillomavirus (PDB ID 6L31)].

Figure 13

Binding free energy plot.

Figure 14

Time frame analysis at every 10 ns of Apigenin complex with L1 protein of human papillomavirus (PDB ID 6L31).

Figure 15

Diagram of the frontier molecular orbital.