Molecular design, synthesis and biological evaluation of cage compound-based inhibitors of hepatitis C virus p7 ion channels
Autor: | Anastasia E. Sibiryakova, Eugene V. Radchenko, Dmitry V. Osipov, Anton V. Lukashenko, M. V. Leonova, Larisa N. Shishkina, Yulia A. Gruzd, Vera A. Shadrikova, M. R. Baimuratov, Vadim A. Shiryaev, Ilya M. Tkachenko, O. A. Serova, E. A. Ivleva, Vladimir A. Palyulin, Alexander N. Reznikov, V. A. Osyanin, Kseniya M. Bormasheva, N. I. Bormotov, Yuri N. Klimochkin, Nikolay S. Zefirov |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Hepatitis C virus Hepacivirus Computational biology medicine.disease_cause Antiviral Agents 01 natural sciences Virus Small Molecule Libraries Viral Proteins 03 medical and health sciences chemistry.chemical_compound Drug Discovery medicine Humans Amino Acid Sequence Homology modeling Binding site NS5A NS5B Pharmacology NS3 010405 organic chemistry Chemistry Organic Chemistry General Medicine Hepatitis C medicine.disease 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology Drug Design Sequence Alignment |
Zdroj: | European Journal of Medicinal Chemistry. 158:214-235 |
ISSN: | 0223-5234 |
Popis: | 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. |
Databáze: | OpenAIRE |
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