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Updated: Oct 20, 2025
05:50
Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
Published on: September 26, 2025
236
SARS-COV-2 Mpro conformational changes induced by covalently bound ligands
Glaucio Monteiro Ferreira1,2, Thales Kronenberger2,3, Arun Kumar Tonduru3
1Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
Journal of Biomolecular Structure & Dynamics
|September 13, 2021
Summary
Molecular dynamics simulations reveal that the dimeric form of SARS-CoV-2 main protease (Mpro) is crucial for understanding ligand interactions and conformational stability, unlike monomeric simulations. This highlights the importance of studying the dimeric structure for drug discovery.
Area of Science:
- Structural Biology
- Computational Chemistry
- Virology
Background:
- SARS-CoV-2 main protease (Mpro) is essential for viral replication.
- Mpro functions as a dimer, but its dimeric conformational changes upon ligand binding are not fully understood.
- Previous studies often focused on monomeric Mpro structures.
Purpose of the Study:
- To investigate the conformational changes and interactions of Mpro-ligand complexes using molecular dynamics (MD).
- To compare the behavior of monomeric and dimeric Mpro simulations.
- To identify key residues involved in ligand interactions and inhibitory activity.
Main Methods:
- Systematic molecular dynamics (MD) simulations of Mpro-ligand complexes (N1 and N3).
- Simulations were performed for both monomeric and dimeric Mpro states (approximately 9 μs per system).
- Comparison of simulated trajectories with the apo (unbound) structure.
Main Results:
- Monomeric Mpro simulations exhibited an unrealistically flexible active site.
- Dimeric Mpro simulations demonstrated a stable oxyanion-loop conformation.
- Specific residues (His41, Gly143, His163, Glu166, Gln189) were identified as critical for ligand interactions, with Gly143 and His163 showing increased interaction frequencies in dimeric simulations.
Conclusions:
- Long-timescale MD simulations are more suitable for studying the activity of bioactive compounds targeting the dimeric form of SARS-CoV-2 Mpro.
- The dimeric state of Mpro is essential for accurate modeling of ligand-induced conformational changes and interactions.
- Understanding dimeric Mpro behavior is key for developing effective antiviral inhibitors.
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