Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease

Biomolecules. 2022 Nov 25;12(12):1754. doi: 10.3390/biom12121754.

Abstract

The recent global health emergency caused by the coronavirus disease 2019 (COVID-19) pandemic has taken a heavy toll, both in terms of lives and economies. Vaccines against the disease have been developed, but the efficiency of vaccination campaigns worldwide has been variable due to challenges regarding production, logistics, distribution and vaccine hesitancy. Furthermore, vaccines are less effective against new variants of the SARS-CoV-2 virus and vaccination-induced immunity fades over time. These challenges and the vaccines' ineffectiveness for the infected population necessitate improved treatment options, including the inhibition of the SARS-CoV-2 main protease (Mpro). Drug repurposing to achieve inhibition could provide an immediate solution for disease management. Here, we used structure-based virtual screening (SBVS) to identify natural products (from NP-lib) and FDA-approved drugs (from e-Drug3D-lib and Drugs-lib) which bind to the Mpro active site with high-affinity and therefore could be designated as potential inhibitors. We prioritized nine candidate inhibitors (e-Drug3D-lib: Ciclesonide, Losartan and Telmisartan; Drugs-lib: Flezelastine, Hesperidin and Niceverine; NP-lib: three natural products) and predicted their half maximum inhibitory concentration using DeepPurpose, a deep learning tool for drug-target interactions. Finally, we experimentally validated Losartan and two of the natural products as in vitro Mpro inhibitors, using a bioluminescence resonance energy transfer (BRET)-based Mpro sensor. Our study suggests that existing drugs and natural products could be explored for the treatment of COVID-19.

Keywords: BRET; COVID-19; FDA-approved drugs; SARS-CoV-2 main protease; deep learning; molecular docking; natural products; structure-based virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacology
  • Biological Products* / chemistry
  • Biological Products* / pharmacology
  • COVID-19*
  • Coronavirus 3C Proteases* / antagonists & inhibitors
  • Coronavirus Protease Inhibitors* / chemistry
  • Coronavirus Protease Inhibitors* / pharmacology
  • Humans
  • Losartan / chemistry
  • Losartan / pharmacology
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • SARS-CoV-2* / drug effects
  • SARS-CoV-2* / enzymology

Substances

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

Grants and funding

This research was supported by College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.