Optimization of SARS-CoV-2 M^pro Inhibitors by a Structure-Based Multilevel Virtual Screening Method

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• The emergence of drug-resistant SARS-CoV-2 strains necessitates the development of novel antiviral therapies.
• The SARS-CoV-2 main protease (M^pro) is a critical target for antiviral drug development.

Purpose of the Study:

• To identify novel, potent, and broad-spectrum inhibitors of SARS-CoV-2 M^pro.
• To evaluate the antiviral activity and mechanism of action of newly synthesized compounds.

Main Methods:

• A fragment-based multilevel virtual screening strategy was employed.
• Hit compounds were synthesized and evaluated for M^pro inhibition and antiviral activity.
• Molecular dynamics simulations were used to analyze drug-target interactions.

Main Results:

• Fifteen hit compounds were synthesized, with A5, A6, and A9 showing potent M^pro inhibition.
• Compound A9 demonstrated significant antiviral activity (EC₅₀ = 0.18 μM), comparable to Nirmatrelvir.
• Molecular dynamics simulations provided insights into the binding interactions of A5, A6, and A9 with SARS-CoV-2 M^pro.

Conclusions:

• Compound A9 is identified as a promising lead for the development of new anti-SARS-CoV-2 drugs.
• The study highlights the potential of targeting SARS-CoV-2 M^pro for effective antiviral therapy.
• Further research is warranted to optimize A9 for clinical application.