Targeting of HPV E6 at the binding sites to the host-cell E6AP, p53, and the endoplasmic reticulum-resident chaperone, GRP78.

Background: Human papillomavirus (HPV) represents an etiological factor for many cancer types, especially cervical cancer. Its oncoprotein E6 sheds drug designers who aim to stop its cellular protein associations, such as p53 and E6AP. Recently, it was discovered that the host-cell chaperone glucose-regulated protein 78 (GRP78) plays a crucial function in HPV infectivity by association with the viral E6 and E7 proteins. Therefore, we aimed to test small molecules inhibitor that could contradict the association between E6 and cellular factors E6AP, GRP78, and p53. Methods: In this study, molecular docking protocol was elaborated to test 115 small molecule compounds against the three binding sites of HPV E6 to the host-cell proteins; E6AP, p53, and GRP78. After that, molecular dynamics simulation and free energy calculations were performed on the best three complexes. Results: The results reveal the potency of 18 compounds against the HPV E6 at different binding sites, which give lower free energies than paclitaxel (positive control). The best two compounds, hypericin, and anabsinthin, could bind effectively and stably during the 100 ns MD simulation period to HPV E6. The calculated average free energies for hypericin and anabsinthin are -18.76 and -14.40 kcal/mol, respectively. They formed stable complexes with the three binding sites by forming hydrophobic contacts. The key residues that stabilize the two ligands in HPV E6 binding sites are V31, Y32, V62, and Y70 (E6AP), P13, C16, T22, I23 and A46 (p53), and M1, V31, L50, L67, and Q107 (GRP78). Conclusions: The best two compounds, hypericin, and anabsinthin, are potential candidates against HPV E6 at the host-cell factors binding sites, hence could block the oncoprotein activity of E6 in infected cells. Further experimental validation is yet to be performed and suggested as future work.Communicated by Ramaswamy H. Sarma.