Hit Expansion of a Noncovalent SARS-CoV-2 Main Protease Inhibitor

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Computational Chemistry

Background:

• Inhibition of SARS-CoV-2 main protease (Mpro) is crucial for COVID-19 drug discovery.
• Non-covalent inhibitors represent a promising therapeutic strategy.

Purpose of the Study:

• To expand the chemical space of non-covalent Mpro inhibitors.
• To identify novel scaffolds with potent inhibitory activity.
• To elucidate binding interactions through structural and computational methods.

Main Methods:

• High-throughput virtual screening of over a billion compounds using molecular fingerprinting.
• Enzyme inhibition assays to evaluate compound activity.
• X-ray crystallography and molecular dynamics simulations to determine binding modes.

Main Results:

• Identified 48 potential inhibitors, with 21 showing activity >50% at 20 μM.
• Four compounds exhibited IC50 values around 1 μM, all containing an isoquinolone motif.
• Determined X-ray structures revealing key interactions with the Mpro active site.

Conclusions:

• The isoquinolone scaffold is effective for non-covalent Mpro inhibition.
• High-throughput computational screening is valuable for drug discovery.
• Results inform lead optimization for developing new COVID-19 therapeutics.