Can molecular dynamics explain decreased pathogenicity in mutant camphecene-resistant influenza virus?

ABSTARCT

The development of new anti-influenza drugs remains an active area, and efforts in this direction will likely continue far into the future. In this paper, we present the results of a theoretical study explaining the mechanisms behind the antiviral activity of camphor derivatives. These include camphecene and a number of its analogues. The compounds tested can inhibit hemagglutinin (HA) by binding to it at two possible sites. Moreover, the binding site located at the site of proteolysis is the most important. Serial passaging of influenza in the presence of camphecene leads to the formation of mutation-associated resistance. Specifically, camphecene causes a significant mutation in HA (V615L). This substitution likely reduces the affinity of the compound for the binding site due to steric restriction of the positioning of camphecene in the binding cavity. Molecular dynamics (MD) simulation results show that the mutant HA is a more stable structure in terms of thermodynamics. In other words, launching conformational rearrangements preceding the transition from pre- to post-fusion requires more energy than in wild type HA. This may well explain the lower virulence seen with the camphecene-resistant strain.

GRAPHICAL ABSTRACTS

Communicated by Ramaswamy H. Sarma

Keywords:

• Camphecene-resistant influenza virus
• hemagglutinin
• camphecene
• molecular docking
• molecular dynamic

Acknowledgements

All calculations were performed on Bioinformatics Laboratory servers (Institute of Translational Medicine and Biotechnology, Sechenov University). Molecular docking and quantum chemical calculations were performed as part of a State Task (AAAA-A17-117011910028-7). Molecular dynamic simulation work was supported by I.M. Sechenov First Moscow State Medical University Strategic Development Program under the Russian Academic Excellence 5–100 Project. The authors express sincere gratitude to Edward Ramsay (Smorodintsev Research Institute of Influenza, St. Petersburg) for his invaluable help in editing and discussion of the manuscript. The authors are grateful to Ministry of Science and Higher Education, Russian Federation for the financial support (grant N 075-15-2020-777).

Disclosure statement

The authors declare no conflict of interest.