2. Academic Validation
  3. In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket

In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket

  • ACS Omega. 2025 Jun 4;10(23):24117-24132. doi: 10.1021/acsomega.4c10519.
Luís Queirós-Reis 1,  Mari Kaarbo̷ 2,  Huda Al-Baldawi 3,  Rui Alvites 1 4 5 6,  Ana Colette Maurício 1 4 5,  Andrea Brancale 7,  Marcella Bassetto 8 9,  João R Mesquita 1 10
Affiliations

Affiliations

  • 1 Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto, Porto 4050-313, Portugal.
  • 2 Department of Microbiology, Oslo University Hospital, Oslo 0424, Norway.
  • 3 Department of Microbiology, University of Oslo, Oslo 0316, Norway.
  • 4 Animal Science Study Centre (CECA), University of Porto Agroenvironment, Technologies and Sciences Institute (ICETA), Porto 4051-401, Portugal.
  • 5 Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), Lisboa 1300-477, Portugal.
  • 6 University Institute of Health Sciences (CESPU), Avenida Central de Gandra 1317, Gandra 4585-116, Portugal.
  • 7 University of Chemistry and Technology, Prague, 166 28 Praha, Czechia.
  • 8 School of Pharmacy and Pharmaceutical Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF10 3BN, U.K.
  • 9 Department of Chemistry, Faculty of Science and Engineering, Swansea University, Swansea SA2 8PP, U.K.
  • 10 Epidemiology Research Unit (EPIunit), Institute of Public Health, University of Porto, Porto 4050-091, Portugal.
PMID: 40547706 DOI: 10.1021/acsomega.4c10519
Abstract

The key viral protein for Infection by SARS-CoV-2 is the spike glycoprotein (S protein), mediating entry into host cells, which therefore represents a strong focus for the development of targeted therapeutics. In this work, we explored the fatty acid binding pocket within the S protein, which stabilizes an inactive conformation and disrupts cell recognition and Infection. To explore the potential of this site as a drug target, molecular dynamics simulations were performed, followed by a docking-based virtual screening of commercial druglike compounds. This in silico procedure enabled the identification of potential inhibitors of SARS-CoV-2 cell Infection, likely by stabilizing an inactive spike conformation, detected in binding assays, although further experiments are required to directly confirm this action. The Antiviral effect of the virtual hits was analyzed in cell-based assays, and one molecule displayed a low micromolar activity. Starting from the best Antiviral compound found, structural analogues were purchased and evaluated in Antiviral assays. An increase in activity was observed for multiple analogues, with the strongest Antiviral compound showing submicromolar activity and low cytotoxicity. The successful identification of a new Antiviral scaffold through in silico studies might pave the way for the further development of antivirals against SARS-CoV-2 and shows the reliability of the methodologies applied.

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