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

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

Журнал

Journal of Biomolecular Structure and Dynamics
ISSN: 0739-1102 , E-ISSN: 1538-0254

Вых. Данные

Год: 2021, DOI: 10.1080/07391102.2020.1871414

Ключевые слова

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

Авторы

Borisevich Sophia S. ¹ , Gureev Maxim A. ² , Yarovaya Olga I. ³ , Zarubaev Vladimir V. ⁴ , Kostin Gennadiy A. ⁵ , Porozov Yuriy B. ^2,6,7 , Salakhutdinov Nariman F. ³

Организации

1	(Данные Web of science) Ufa Inst Chem UFRS RAS, Lab Phys Chem, Ufa, Russia
2	(Данные Web of science) IM Sechenov First Moscow State Med Univ, Lab Bioinformat, Moscow, Russia
3	(Данные Web of science) Siberian Branch RAS, NN Vorozhtsov Novosibirsk Inst Organ Chem, Dept Med Chem, Novosibirsk, Russia
4	(Данные Web of science) St Petersburg Pasteur Inst, Dept Virol, St Petersburg, Russia
5	(Данные Web of science) Nikolaev Inst Inorgan Chem SB RAS, Novosibirsk, Russia
6	(Данные Web of science) ITMO Univ, Dept Food Biotechnol & Engn, St Petersburg, Russia
7	(Данные Web of science) Sirius Univ Sci & Technol, Dept Computat Biol, Soci, Russia

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.

Borisevich S.S. , Gureev M.A. , Yarovaya O.I. , Zarubaev V.V. , Kostin G.A. , Porozov Y.B. , Salakhutdinov N.F.
Can molecular dynamics explain decreased pathogenicity in mutant camphecene-resistant influenza virus?
Journal of Biomolecular Structure and Dynamics. 2021. DOI: 10.1080/07391102.2020.1871414 WOS Scopus

Опубликована online:

22 янв. 2021 г.

Web of science	WOS:000609588300001
Scopus	2-s2.0-85099741964
OpenAlex	W3122655214