De novo design of SARS-CoV-2 main protease inhibitors with characteristic binding modes

Structure. 2024 Sep 5;32(9):1327-1334.e3. doi: 10.1016/j.str.2024.05.019. Epub 2024 Jun 25.

Abstract

The coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spreads rapidly all over the world. The main protease (Mpro) is significant to the replication and transcription of viruses, making it an attractive drug target against coronaviruses. Here, we introduce a series of novel inhibitors which are designed de novo through structure-based drug design approach that have great potential to inhibit SARS-CoV-2 Mproin vitro. High-resolution structures show that these inhibitors form covalent bonds with the catalytic cysteine through the novel dibromomethyl ketone (DBMK) as a reactive warhead. At the same time, the designed phenyl group beside the DBMK warhead inserts into the cleft between H41 and C145 through π-π stacking interaction, splitting the catalytic dyad and disrupting proton transfer. This unique binding model provides novel clues for the cysteine protease inhibitor development of SARS-CoV-2 as well as other pathogens.

Keywords: SARS-CoV-2; coronavirus; drug resistance; inhibitor; main protease.

MeSH terms

  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacology
  • Binding Sites
  • COVID-19 Drug Treatment
  • Catalytic Domain
  • Coronavirus 3C Proteases* / antagonists & inhibitors
  • Coronavirus 3C Proteases* / chemistry
  • Coronavirus 3C Proteases* / metabolism
  • Crystallography, X-Ray
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Protease Inhibitors* / chemistry
  • Protease Inhibitors* / metabolism
  • Protease Inhibitors* / pharmacology
  • Protein Binding*
  • SARS-CoV-2* / drug effects
  • SARS-CoV-2* / enzymology
  • SARS-CoV-2* / metabolism

Substances

  • Coronavirus 3C Proteases
  • Protease Inhibitors
  • Antiviral Agents
  • 3C-like proteinase, SARS-CoV-2