Rational Approach toward COVID-19's Main Protease Inhibitors: A Hierarchical Biochemoinformatics Analysis

Area of Science:

• Computational chemistry
• Drug discovery
• Virology

Background:

• SARS-CoV-2 main protease (M^pro) is a critical target for antiviral drug development.
• Identifying potent and stable M^pro inhibitors is essential for combating COVID-19.

Purpose of the Study:

• To evaluate potential SARS-CoV-2 M^pro inhibitors using in silico methods.
• To assess the binding affinity, stability, and interaction patterns of selected compounds with M^pro.

Main Methods:

• In silico molecular docking and molecular dynamics (MD) simulations.
• Pharmacokinetic and toxicological analyses.
• MM-PBSA calculations and hydrogen bond analysis during MD.

Main Results:

• Docking revealed ligands with high binding affinities (-6.2 to -9.5 kcal/mol).
• MD simulations confirmed stable protein-ligand complexes over 200 ns.
• MM-PBSA indicated favorable binding energies and consistent hydrogen bonding with M^pro catalytic residues.

Conclusions:

• Selected compounds exhibit significant potential as SARS-CoV-2 M^pro inhibitors.
• These findings support further investigation for developing novel COVID-19 therapeutics.