Elucidating Molecular Interactions of Natural Inhibitors with HPV-16 E6 Oncoprotein through Docking Analysis

Abstract

Human papillomavirus (HPV) infection is the leading cause of cancer mortality among women worldwide. The life-threatening infection caused by HPV demands the need for designing anticancerous drugs. In the recent years, different compounds from natural origins, such as carrageenan, curcumin, epigallocatechin gallate, indole-3-carbinol, jaceosidin, and withaferin, have been used as a hopeful source of anticancer therapy. These compounds have been shown to suppress HPV infection by different researchers. In the present study, we explored these natural inhibitors against E6 oncoprotein of high-risk HPV-16, which is known to inactivate the p53 tumor suppressor protein. A robust homology model of HPV-16 E6 was built to anticipate the interaction mechanism of E6 oncoprotein with natural inhibitory molecules using a structure-based drug designing approach. Docking analysis showed the interaction of these natural compounds with the p53-binding site of E6 protein residues 113-122 (CQKPLCPEEK) and helped the restoration of p53 functioning. Docking analysis, besides helping in silico validation of natural compounds, also helps understand molecular mechanisms of protein-ligand interactions.

Identification of HPV16 in suspected cases of cervical lesions and docking Study of its L1 protein with some natural inhibitors.

“…All the compounds were found to inhibit strongly by completely occupying the active sites in the target protein (2r5h), in this study the inhibitors is occupied within the AA 50-60 of the L1 protein, which is situated in the DE-Loop of the HPV L1 proteın. Most of the ligands were found to be having polar contact with the receptor (2r5h).The best two docking results were zinc_33737268 (chicoric acid) with a binding energy of -8.7 kcal/mol which is lower than the binding energy reported for Wıthaferin A docked against HPV E6 protein in a study by Kumar et al (2014), though in the same study carrageenan showed a much lower binding energy when docked agaınst E6 protein, but the present study targeted the L1 protein which is a more conserved region, the L1 also has the heparin binding site in its loop, which plays important role in high risk HPV…”

“…Non-polar hydrogen were added to the docked ligands. For Lamarckıan genetic algorithm, a maximum number of 15 × 10 5 energy evaluations, 27,000 maximum generations, 0.02 gene mutation rate and 0.8 crossover rate were used [18]. Each ligands has had two hundred independent docking runs.…”

Antitumour effects of metformin and curcumin in human papillomavirus positive and negative head and neck cancer cells

“…The potential explanation for the discrepancy in p53 expression after treatment in the HPV+ cell lines may lie with the agent’s ability to regulate viral oncoprotein expression. The comparable expression of p53 to control groups in the HPV+ cells upon treatment with curcumin may be due to curcumin’s ability to downregulate viral oncoprotein HPV‐E6, which has historically bound and inhibited p53 function via ubiquitination and degradation . However, metformin’s interactions with HPV viral oncoproteins are currently unknown and would require further investigation before any conclusions can be made.…”

The in Silico Approach to Identifying a Unique Plant-Derived Inhibitor Against E6 and E7 Oncogenic Proteins of High-Risk Human Papillomavirus 16 and 18

“…The active site of the model was analyzed based on the docking interaction between the p53 and pRb binding site residues (12)(13)(14)(18)(19)(20) of HPV oncoproteins, and all natural ligands.…”

“…In our previous study, we already described the positive results of using curcumin, epigallocatechin-3-gallate (EGCG), jaceosidin (12)(13)(14), resveratrol (13,14), indole-3-carbinol, withaferin A (12,14), artemisinin, ursolic acid, ferulic acid, berberin, resveratrol, gingerol, and silymarin (14) as indications that these compounds are possible effective sources of cancer treatment. …”