Small Molecules Targeting SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain

Area of Science:

• Virology
• Drug Discovery
• Structural Biology

Background:

• The ongoing COVID-19 pandemic is driven by SARS-CoV-2 variants with altered transmissibility and infectivity.
• Mutations in the viral spike (S) glycoprotein affect its interaction with the human ACE2 receptor, facilitating viral entry.
• Despite vaccine development, there is a critical need for selective antiviral agents targeting the S glycoprotein.

Purpose of the Study:

• To identify small molecules capable of disrupting the SARS-CoV-2 S glycoprotein-hACE2 interaction.
• To inhibit viral entry into host cells using structure-based drug design.
• To evaluate the antiviral activity of potential drug candidates against SARS-CoV-2.

Main Methods:

• Analysis of the S glycoprotein-hACE2 complex structure (PDB: 7DF4) and modeling of viral variants using VMD and MOE.
• Structure-based virtual screening of small molecules against S glycoprotein models using OEDocking FRED-4.0.0.0.
• Ranking of small molecules by affinity using the FRED-4.0.0.0 Chemguass4 scoring function.
• Antiviral testing of selected compounds using a SARS-CoV-2 pseudotyped cell-based bioassay.

Main Results:

• Virtual screening identified candidate small molecules targeting the S glycoprotein.
• Three selected compounds exhibited significant antiviral selectivity in cell-based assays.
• Combinations of these compounds also demonstrated antiviral effects.

Conclusions:

• Small molecules can be designed to inhibit SARS-CoV-2 entry by targeting the S glycoprotein-hACE2 interaction.
• Identified compounds show promise as potential therapeutic agents for COVID-19.
• These molecules may also serve as valuable tools for further research into SARS-CoV-2 biology.