Разработка противовирусных лекарств на основе ингибиторов главной протеазы SARS-CoV-2

Translated title of the contribution: Development of antiviral drugs based on inhibitors of the sars-CoV-2 main protease

A. V. Sulimov, Kh S. Shikhaliev, O. V. Pyankov, D. N. Shcherbakov, V. Yu Chirkova, I. S. Ilin, D. C. Kutov, A. S. Tashchilova, M. Yu Krysin, D. V. Krylskiy, N. V. Stolpovskaya, E. A. Volosnikova, S. V. Belenkaya, V. B. Sulimov

Research output: Contribution to journalArticlepeer-review

Abstract

Docking and quantum-chemical methods have been used for screening of drug-like compounds from the own database of the Voronezh State University to find inhibitors the SARS-CoV-2 main protease, an important enzyme of the coronavirus responsible for the COVID-19 pandemic. Using the SOL program more than 42000 3D molecular structures were docked into the active site of the main protease, and more than 1000 ligands with most negative values of the SOL score were selected for further processing. For all these top ligands, the protein-ligand binding enthalpy has been calculated using the PM7 semiempirical quantum-chemical method with the COSMO implicit solvent model. 20 ligands with the most negative SOL scores and the most negative binding enthalpies have been selected for further experimental testing. The latter has been made by measurements of the inhibitory activity against the main protease and suppression of SARS-CoV-2 replication in a cell culture. The inhibitory activity of the compounds was determined using a synthetic fluorescently labeled peptide substrate including the proteolysis site of the main protease. The antiviral activity was tested against SARS-CoV-2 virus in the Vero cell culture. Eight compounds showed inhibitory activity against the main protease of SARS-CoV-2 in the submicromolar and micromolar ranges of the IC50 values. Three compounds suppressed coronavirus replication in the cell culture at the micromolar range of EC50 values and had low cytotoxicity. The found chemically diverse inhibitors can be used for optimization in order to obtain a leader compound, the basis of new direct-acting antiviral drugs against the SARS-CoV-2 coronavirus.

Translated title of the contributionDevelopment of antiviral drugs based on inhibitors of the sars-CoV-2 main protease
Original languageRussian
Article number9
Pages (from-to)259-267
Number of pages9
JournalBiomeditsinskaya Khimiya
Volume67
Issue number3
DOIs
Publication statusPublished - May 2021

Keywords

  • Antiviral drugs
  • CADD
  • COVID-19
  • Docking
  • Drug discovery
  • Inhibitors
  • M
  • Quantum chemistry
  • SARS-CoV-2

OECD FOS+WOS

  • 1.06 BIOLOGICAL SCIENCES

State classification of scientific and technological information

  • 31 CHEMISTRY

Fingerprint

Dive into the research topics of 'Development of antiviral drugs based on inhibitors of the sars-CoV-2 main protease'. Together they form a unique fingerprint.

Cite this