Consensus Pharmacophore Strategy For Identifying Novel SARS-Cov-2 M^pro Inhibitors from Large Chemical Libraries

Area of Science:

• * Computational chemistry and structural biology.
• * Drug discovery and medicinal chemistry.

Background:

• * The SARS-CoV-2 main Protease (Mpro) is essential for viral replication and a key drug target.
• * Existing Mpro inhibitors are often based on known crystal structures, limiting chemical diversity.

Purpose of the Study:

• * To develop a Mpro consensus pharmacophore model for broader inhibitor screening.
• * To identify novel chemical scaffolds with Mpro inhibitory activity.

Main Methods:

• * Generated a consensus pharmacophore model from 152 bioactive conformers of Mpro inhibitors.
• * Validated the model's accuracy in reproducing crystal-binding modes (77% success rate).
• * Screened over 340 million compounds using pharmacophore matching and chemoinformatics.

Main Results:

• * Identified novel Mpro inhibitor candidates chemically distinct from known inhibitors.
• * Evaluated 16 candidates, with seven demonstrating Mpro enzymatic inhibitory activity.
• * Three compounds exhibited mid-micromolar IC50 values.

Conclusions:

• * The consensus pharmacophore is a valuable tool for discovering diverse Mpro inhibitors.
• * The developed method and open-access code can be applied to other drug targets.
• * This approach facilitates the identification of compounds with improved activity and novel scaffolds.