Fragment-based design and MD simulations of human papilloma virus-16 E6 protein inhibitors

Abstract

The main objective of this study is to screen potential small molecule inhibitors against HPV (Human Papilloma Virus)-16 E6 protein (HPV16 E6P) using a fragment-based approach. Twenty-six natural HPV inhibitors were selected based on the review of the literature. Among them, Luteolin was selected as the reference compound. These 26 compounds were used to generate novel inhibitors against HPV16 E6P. Fragment script and BREED of Schrodinger software were used to build novel inhibitor molecules. The result in 817 novel molecules was docked into the active binding site of HPV E6 protein and the top ten compounds were screened based on binding affinity compared to Luteolin for further study. Compounds Cpd5, Cpd7, and Cpd10 were the most potent inhibitors of HPV16 E6P and these were non-toxic and showed high Gastrointestinal (GI) absorption and positive drug-likeness score. Complexes of these compounds were stable in the 200 ns Molecular Dynamics (MD) simulation. These 3 HPV16 E6P inhibitors could be the lead molecules as new drugs for HPV-related diseases.

Communicated by Ramaswamy H. Sarma

Keywords:

• ADME
• anti-cervical cancer
• BREED
• fragmentation
• HPV16 E6P
• molecular docking

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors wish to place on record sincere thanks to the Management of Gokula Education Foundation, M.S. Ramaiah College of Arts, Science, and Commerce, Bengaluru-560054, India, for sponsoring this project through seed funding (Ref. No.: PO/CIR/2020-21/017) and also thanking the Principal, Head of the Department and the faculty of Department of Microbiology of the college for their support and cooperation during this work.