Elucidating Molecular Interactions of Ten Natural Compounds Targeting E6 HPV High Risk Oncoproteins Using Microsecond Molecular Dynamics Simulations.

Abstract

Cervical cancer is a major public health issue worldwide, occurring in the vast majority of cases (85%) in low-income countries. Human papillomavirus (HPV) mainly infects the mucosal epithelium, and a small portion causes over 600,000 cases every year worldwide at various anatomical spots, mainly leading to anogenital and head and neck. The E6 oncoprotein encoded by cancer-associated alpha HPV can transform epithelial cells into tumorigenic tissue. Therapy for this infection and blocking of the HPV E6 oncoprotein could be provided with cost-effective and abundant natural products which are an exponentially growing topic in the literature. Finding an active natural compound that readily blocks HPV E6 oncoprotein which could be available for developing countries without expensive extraction processes or costly synthetic pathways is of major interest. Molecular dynamics simulation was performed using the most up-to-date AMBER protein force field ff14SB and a GPU enabled high performance computing cluster. In this research, we present a study of the binding properties between 10 selected natural compounds that are readily available with two variants of the E6 oncoprotein types (HPV-16 and HPV-18) using 10+ microsecond molecular dynamics simulations. Our results suggest that crocetin, ergosterol peroxide and κ-carrageenan natural products bind strongly to both HPV-16 and HPV-18 and could potentially serve as a scaffolding for further drug development.