Targeting the SARS-CoV-2 spike glycoprotein prefusion conformation: virtual screening and molecular dynamics simulations applied to the identification of potential fusion inhibitors

Virus Res. 2020 Sep;286:198068. doi: 10.1016/j.virusres.2020.198068. Epub 2020 Jun 18.


The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a renewed interest in studying the role of the spike S glycoprotein in regulating coronavirus infections in the natural host. Taking advantage of the cryo-electron microscopy structure of SARS-CoV-2 S trimer in the prefusion conformation, we performed a virtual screening simulation with the aim to identify novel molecules that could be used as fusion inhibitors. The spike glycoprotein structure has been completed using modeling techniques and its inner cavity, needful for the postfusion transition of the trimer, has been scanned for the identification of strongly interacting available drugs. Finally, the stability of the protein-drug top complexes has been tested using classical molecular dynamics simulations. The free energy of interaction of the molecules to the spike protein has been evaluated through the MM/GBSA method and per-residue decomposition analysis. Results have been critically discussed considering previous scientific knowledge concerning the selected compounds and sequence alignments have been carried out to evaluate the spike glycoprotein similarity among the betacoronavirus family members. Finally, a cocktail of drugs that may be used as SARS-CoV-2 fusion inhibitors has been suggested.

Keywords: Fusion inhibitors; Molecular dynamics; SARS-CoV-2; Sequence alignment; Spike glycoprotein; Virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracenes
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology
  • Betacoronavirus / chemistry*
  • Betacoronavirus / pathogenicity
  • Binding Sites
  • COVID-19
  • Coronavirus Infections / drug therapy
  • Coronavirus Infections / virology
  • Gene Expression
  • Heterocyclic Compounds, 4 or More Rings / chemistry*
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • High-Throughput Screening Assays
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacology
  • Isoindoles
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Pandemics
  • Perylene / analogs & derivatives*
  • Perylene / chemistry
  • Perylene / pharmacology
  • Pneumonia, Viral / drug therapy
  • Pneumonia, Viral / virology
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • SARS-CoV-2
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Spike Glycoprotein, Coronavirus / antagonists & inhibitors
  • Spike Glycoprotein, Coronavirus / chemistry*
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / metabolism
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology
  • Thermodynamics
  • User-Computer Interface
  • Virus Internalization / drug effects


  • 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione
  • Anthracenes
  • Antiviral Agents
  • Heterocyclic Compounds, 4 or More Rings
  • Indoles
  • Isoindoles
  • Small Molecule Libraries
  • Spike Glycoprotein, Coronavirus
  • Sulfonamides
  • spike protein, SARS-CoV-2
  • Perylene
  • hypericin
  • phthalocyanine