Structure-based virtual screening and molecular dynamics simulation studies to discover new SARS-CoV-2 main protease...

Area of Science:

• Medicinal Chemistry
• Computational Drug Discovery
• Structural Biology

Background:

• The M^PRO (main protease) is a critical target for antiviral drug development.
• Existing inhibitors may have suboptimal binding affinity or interactions.

Purpose of the Study:

• To computationally identify novel M^PRO inhibitors with enhanced binding affinity and specific interactions.
• To evaluate the stability of identified compounds using molecular dynamics simulations.

Main Methods:

• Virtual screening of over 8,000 compounds against M^PRO.
• Filtering based on binding affinity and interaction with the catalytic dyad (Cys145 and His41).
• Ranking, reranking, and 50 ns molecular dynamics (MD) simulations.

Main Results:

• Eleven compounds met the initial screening criteria.
• Common structural features critical for M^PRO interaction were identified.
• AV-203 demonstrated the highest affinity (Ki = 0.31 µM) and stable binding during MD simulation.

Conclusions:

• AV-203 is a potent M^PRO inhibitor with stable binding characteristics.
• AV-203 serves as a suitable lead compound for further antiviral drug development.