Ginkgolic acids inhibit SARS-CoV-2 and its variants by blocking the spike protein/ACE2 interplay

Int J Biol Macromol. 2023 Jan 31;226:780-792. doi: 10.1016/j.ijbiomac.2022.12.057. Epub 2022 Dec 12.


Targeting the interaction between the spike protein receptor binding domain (S-RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and angiotensin-converting enzyme 2 (ACE2) is a potential therapeutic strategy for treating coronavirus disease 2019 (COVID-19). However, we still lack small-molecule drug candidates for this target due to the missing knowledge in the hot spots for the protein-protein interaction. Here, we used NanoBiT technology to identify three Ginkgolic acids from an in-house traditional Chinese medicine (TCM) library, and they interfere with the S-RBD/ACE2 interplay. Our pseudovirus assay showed that one of the compounds, Ginkgolic acid C17:1 (GA171), significantly inhibits the entry of original SARS-CoV-2 and its variants into the ACE2-overexpressed HEK293T cells. We investigated and proposed the binding sites of GA171 on S-RBD by combining molecular docking and molecular dynamics simulations. Site-directed mutagenesis and surface plasmon resonance revealed that GA171 specifically binds to the pocket near R403 and Y505, critical residues of S-RBD for S-RBD interacting with ACE2. Thus, we provide structural insights into developing new small-molecule inhibitors and vaccines against the proposed S-RBD binding site.

Keywords: Ginkgolic acid; S-RBD; SARS-CoV-2.

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • COVID-19*
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • SARS-CoV-2*
  • Spike Glycoprotein, Coronavirus / genetics


  • Angiotensin-Converting Enzyme 2
  • ginkgolic acid
  • spike protein, SARS-CoV-2
  • Spike Glycoprotein, Coronavirus