Targeting SARS-CoV-2 M3CLpro by HCV NS3/4a Inhibitors: In Silico Modeling and In Vitro Screening

Area of Science:

• Biochemistry
• Virology
• Drug Discovery

Background:

• The COVID-19 pandemic, caused by SARS-CoV-2, necessitates the development of effective antiviral therapies.
• The coronavirus main cysteine protease (M3CLpro) is crucial for viral replication and represents a promising drug target.

Purpose of the Study:

• To investigate the binding dynamics of M3CLpro with ligands.
• To evaluate the inhibitory potential of existing hepatitis C virus (HCV) protease inhibitors against M3CLpro.
• To provide insights for designing novel SARS-CoV-2 protease inhibitors.

Main Methods:

• X-ray crystallography of M3CLpro with boceprevir.
• Molecular dynamics (MD) simulations to analyze ligand binding and the chemical environment.
• In vitro testing of HCV NS3/4a protease inhibitors against M3CLpro.
• Molecular docking studies.

Main Results:

• Boceprevir binding induces dynamic changes in M3CLpro.
• Several HCV NS3/4a protease inhibitors, including asunaprevir, narlaprevir, paritaprevir, simeprevir, and telaprevir, demonstrated significant in vitro inhibitory activity against M3CLpro.
• MD simulations and molecular docking provided insights into ligand-protease interactions.

Conclusions:

• Existing HCV protease inhibitors show promise for repurposing against SARS-CoV-2.
• Understanding M3CLpro-ligand interactions can guide the development of potent COVID-19 antiviral drugs.