An integrative computational study of marine natural products as selective inhibitors of HPV16 and HPV18 E6/E7 oncoproteins: structural and energetic insights from PCA-based free energy landscape analysis

Human papillomavirus (HPV) is a well-established causative agent in cervical as well as in a few other anogenital and oropharyngeal cancers. Of the many genotypes, HPV16 and HPV18 are the most oncogenic, individually responsible for more than half of all cervical cancer cases worldwide. In the current study, a structure-based computational strategy was used to search for candidate small-molecule inhibitors for the E6 and E7 proteins of HPV16 and HPV18. A subset of ligands was subjected to molecular docking to assess their binding affinities at the oncoprotein active sites. Validation of structural stability of the docked complexes was carried out using molecular dynamics (MD) simulation and PCA based FEL analysis under physiological conditions. In addition, the ADMET and toxicity profiles of both compounds were also predicted with ProTox-III based on top parameters. This integrative overview allowed for the recognition of promising lead compounds possessing favorable binding properties, structural integrity, and low predicted toxicity.