Molecular design, synthesis and biological evaluation of cage compound-based inhibitors of hepatitis C virus p7 ion channels

Shiryaev, V.A.; Radchenko, E.V.; Palyulin, V.A.; Zefirov, N.S.; Bormotov, N.I.; Serova, O.A.; Shishkina, L.N.; Baimuratov, M.R.; Bormasheva, K.M.; Gruzd, Y.A.; Ivleva, E.A.; Leonova, M.V.; Lukashenko, A.V.; Osipov, D.V.; Osyanin, V.A.; Reznikov, A.N.; Shadrikova, V.A.; Sibiryakova, A.E.; Tkachenko, I.M.; Klimochkin, Y.N.

Авторы: Shiryaev V.A., Radchenko E.V., Palyulin V.A., Zefirov N.S., Bormotov N.I., Serova O.A., Shishkina L.N., Baimuratov M.R., Bormasheva K.M., Gruzd Y.A., Ivleva E.A., Leonova M.V., Lukashenko A.V., Osipov D.V., Osyanin V.A., Reznikov A.N., Shadrikova V.A., Sibiryakova A.E., Tkachenko I.M., Klimochkin Y.N.
Журнал: European Journal of Medicinal Chemistry
Том: 158
Год издания: 2018
Издательство: Elsevier BV
Местоположение издательства: Netherlands
Первая страница: 214
Последняя страница: 235
DOI: 10.1016/j.ejmech.2018.08.009
Аннотация: Highlights: Hepatitis C virus p7 viroporin is an attractive target for the cage-based inhibitors; Potential broad-spectrum inhibitors were designed by molecular modeling and dynamics; 53 compounds were synthesized and tested for antiviral activity in BVDV model; Results demonstrate potential therapeutic usefulness and encourage detailed studies. ==== The hepatitis C caused by the hepatitis C virus (HCV) is an acute and/or chronic liver disease ranging in severity from a mild brief ailment to a serious lifelong illness that affects up to 3% of the world population and imposes significant and increasing social, economic, and humanistic burden. Over the past decade, its treatment was revolutionized by the development and introduction into clinical practice of the direct acting antiviral (DAA) agents targeting the non-structural viral proteins NS3/4A, NS5A, and NS5B. However, the current treatment options still have important limitations, thus, the development of new classes of DAAs acting on different viral targets and having better pharmacological profile is highly desirable. The hepatitis C virus p7 viroporin is a relatively small hydrophobic oligomeric viral ion channel that plays a critical role during virus assembly and maturation, making it an attractive and validated target for the development of the cage compound-based inhibitors. Using the homology modeling, molecular dynamics, and molecular docking techniques, we have built a representative set of models of the hepatitis C virus p7 ion channels (Gt1a, Gt1b, Gt1b_L20F, Gt2a, and Gt2b), analyzed the inhibitor binding sites, and identified a number of potential broad-spectrum inhibitor structures targeting them. For one promising compound, the binding to these targets was additionally confirmed and the binding modes and probable mechanisms of action were clarified by the molecular dynamics simulations. A number of compounds were synthesized, and the tests of their antiviral activity (using the BVDV model) and cytotoxicity demonstrate their potential therapeutic usefulness and encourage further more detailed studies. The proposed approach is also suitable for the design of broad-spectrum ligands interacting with other multiple labile targets including various viroporins.
Добавил в систему: Радченко Евгений Валерьевич

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Molecular design, synthesis and biological evaluation of cage compound-based inhibitors of hepatitis C virus p7 ion channelsстатья