Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against...

Area of Science:

• Drug discovery and development
• Virology
• Computational chemistry

Background:

• The COVID-19 pandemic highlighted the urgent need for antiviral drugs targeting SARS-CoV-2.
• Developing inhibitors of the SARS-CoV-2 main protease is critical for pandemic preparedness.

Purpose of the Study:

• To identify novel inhibitors of the SARS-CoV-2 main protease using virtual screening.
• To optimize lead compounds for potent antiviral activity and favorable pharmacokinetic properties.

Main Methods:

• Structure-based virtual screening of a 235-million-compound library against the SARS-CoV-2 main protease active site.
• Experimental validation including binding assays, enzymatic assays, and crystallographic studies.
• Fragment-based drug design incorporating docking and iterative experimental testing.

Main Results:

• Three potential inhibitors were identified from the initial virtual screen.
• Five optimized fragment compounds demonstrated significant inhibitory effects.
• A noncovalent inhibitor with nanomolar affinity and broad-spectrum antiviral activity in cells was developed.

Conclusions:

• Virtual screening strategies are effective for discovering SARS-CoV-2 main protease inhibitors.
• Hit-to-lead optimization guided by structural data yielded a potent antiviral candidate.
• The identified inhibitors show promise for future therapeutic development against coronaviruses.