In-silico molecular modeling studies to identify novel Potential inhibitors of HPV E6 protein

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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, 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 based on virtual screening and prediction of the ADME properties of the molecules and the docking with E6 protein, likewise, their stability in the docked E6 complex and their effect in inhibiting the E6-E6AP interaction was determined. In contrast, the identified molecules were selected. Their stability in the E6 complex and their inhibitory effect on the E6-E6AP interaction were confirmed by molecular dynamics (MD) simulation. Hence, the identified molecules represent a good starting point for the development of anti-HPV drugs.

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