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Fusion inhibitors of tick-borne flaviviruses: identification and mode of action studyтезисы доклада
- Авторы: Dueva E.V., Osolodkin D.I., Kozlovskaya L.I., Karganova G.G., Palyulin V.A., Zefirov N.S.
- Сборник: 21st European Symposium on Quantitative Structure-Activity Relationship: Where Molecular Simulations Meet Drug Discovery, Verona, Italy, September 4-8, 2016
- Тезисы
- Год издания: 2016
- Место издания: Verona, Italy
- Первая страница: OC23
- Аннотация: Flaviviruses comprise a large group of enveloped viruses, causing human diseases all over the world. In the recent years more flaviviruses became a public health emergency concern. The most known among them are dengue virus, Zika virus, tick-borne encephalitis virus (TBEV), etc. Despite vaccines exist against some of them there are no approved drugs, which could be applied after infection. One of the prominent antiviral drug design approaches is the inhibition of fusion between the host cell and viral membranes, driven by low pH-rearrangements of the viral envelope proteins, which results in the release of viral genetic material into cytoplasm. Homology models of E protein ectodomain dimer in the closed and open hydrophobic pocket states, differing by the position of the kl loop, were constructed for TBEV and closely related Powassan virus, using Modeller9v10. The docking-based virtual screening of chemical databases against hydrophobic pocket of the envelope protein models with the help of OpenEye FRED program [1] revealed several putative hit compounds. A number of reproduction inhibitors belonging to the series of 1,4-dihydropyridines, 1,3,5-thiadiazolines, and 4-aminotetrahydroquinazolines were identified among them during in vitro studies [2,3]. The time-of-addition assay confirmed the compounds to be involved in disruption of virion – cell surface interactions prior to or at the stage of the virion entry into the host cell. Representatives of 4-aminotetrahydroquinazolines class revealed activity against broad spectrum of TBEV strains. Their activity turned out to depend stronger not on amino acid composition of to the binding site, but on the ratio of infectious and non-infectious virus particles. Molecular dynamics simulations shed the light onto the character of interaction between the Powassan virus reproduction inhibitors and envelope proteins. The pattern of the protein movement changed when the inhibitoris present, and such changes could be coupled to the inhibition of the reproduction of flaviviruses. MD simulations with protonated histidine residues correspond to the experimental data obtained for the related viruses [4].
- Добавил в систему: Радченко Евгений Валерьевич