In-Silico Molecular Modeling Studies to Identify Novel Potential Inhibitors of HPV E6 Protein

Abstract

The etiological agent of some anogenital tract cancers is infection with the high-risk human papillomavirus (HPV). Currently, prophylactic vaccines against HPV have been validated, but the presence of drug treatment directed against the infection and its oncogenic effects remain essential. Among the best drug targets, viral oncoprotein E6 has been identified as a key factor in cell immortalization and tumor progression in HPV-positive cells. E6, through interaction with the cellular ubiquitin ligase E6AP, can promote the degradation of p53, a tumor suppressor protein. Therefore, suppression of the creation of the E6-E6AP complex is one of the essential strategies to inhibit the survival and proliferation of infected cells. In the present study, we proposed an in-silico approach for the discovery of small molecules with inhibitory activity on the E6-E6AP interaction. The first three compounds (F0679-0355, F33774-0275, and F3345-0326) were selected on the basis of virtual screening and prediction of the molecules' ADMET properties and docking with E6 protein, these molecules were selected for further study by investigating their stability in the E6 complex and their inhibitory effect on the E6-E6AP interaction by molecular dynamics (MD) simulation. The identified molecules thus represent a good starting point for the development of anti-HPV drugs.

Keywords: ADMET properties; E6-E6AP; MD simulations; cervical cancer; docking; virtual screening.

Figure 1

Structure of the top identified lead compounds.

Figure 1

Structure of the top identified lead compounds.

Figure 2

Positioning and interactions of the molecule F0679-0355 inside the active site of receptor HPV16E6 (PDB ID 4xr8).

Figure 3

Positioning and interactions of the molecule F3345-0326 inside the active site of receptor HPV16E6 (PDB ID 4xr8).

Figure 4

Positioning and interactions of the molecule F3374-0275 inside the active site of receptor HPV16E6 (PDB ID 4xr8).

Figure 5

Root means square deviation (RMSD) of the C-alpha atoms of protein and the ligand with time. The left Y-axis shows the variation of protein RMSD through time. The right Y-axis shows the variation of ligand RMSD through time. (A) RMSD of F0679-0355_4xr8 complex. (B) RMSD of F3374-0275_4xr8 complex. (C) RMSD of F3345-0326_4xr8 complex.

Figure 5

Root means square deviation (RMSD) of the C-alpha atoms of protein and the ligand with time. The left Y-axis shows the variation of protein RMSD through time. The right Y-axis shows the variation of ligand RMSD through time. (A) RMSD of F0679-0355_4xr8 complex. (B) RMSD of F3374-0275_4xr8 complex. (C) RMSD of F3345-0326_4xr8 complex.

Figure 6

Residue wise Root Mean Square Fluctuation (RMSF) of protein with F0679-0355 (A), F3374-0275 (B), and F3345-0326 (C) ligands.

Figure 6

Residue wise Root Mean Square Fluctuation (RMSF) of protein with F0679-0355 (A), F3374-0275 (B), and F3345-0326 (C) ligands.

Figure 7

Distribution of protein secondary structure components by residue index across the protein structure. Red denotes alpha helices, and blue denotes beta-strands.

Figure 7

Distribution of protein secondary structure components by residue index across the protein structure. Red denotes alpha helices, and blue denotes beta-strands.

Figure 8

Protein–ligand contact histogram.

Figure 8

Protein–ligand contact histogram.