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Updated: May 9, 2026
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Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
Published on: September 26, 2025
Integrated computational protocol for sampling molecular databases towards allosteric inhibition of SARS-CoV-2 spike
Vanda Boršová1, Dávid Zajaček1, Lukas Bucinsky1
1Faculty of Chemical and Food Technology, Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology, Bratislava, Slovakia.
Journal of Biomolecular Structure & Dynamics
|May 8, 2026
Summary
Researchers computationally screened small molecules to find those that could block SARS-CoV-2 spike protein opening, a key step for viral entry. Medium-sized molecules showed the most promise in stabilizing the protein, offering a new strategy against viral infections.
Area of Science:
- Biophysics
- Computational Chemistry
- Virology
Background:
- The SARS-CoV-2 spike (S) glycoprotein's receptor-binding domain (RBD) must open for viral entry.
- Understanding allosteric modulation of this conformational change is crucial for antiviral drug discovery.
Purpose of the Study:
- To computationally screen small molecules for their ability to allosterically inhibit the opening of the SARS-CoV-2 RBD.
- To identify molecular features that influence the allosteric modulation of viral fusion proteins.
Main Methods:
- Integrated computational approach including virtual screening of the ZINC database (∼60,000 compounds).
- Physicochemical, absorption, and spatial filtering to identify candidate molecules.
- Molecular dynamics (MD) simulations, including steered MD and umbrella sampling, to assess ligand stability and effects on RBD opening.
- Principal component analysis (PCA) for conformational analysis.
Main Results:
- 739 candidate compounds were identified from the initial screen, with nine representatives selected for detailed simulation.
- MD simulations revealed varying ligand stability and distinct effects on RBD opening dynamics.
- Free-energy profiles and PCA maps indicated that medium-sized ligands most consistently stabilized the RBD, while larger ligands significantly altered the activation pathway.
Conclusions:
- The study presents a practical computational framework for evaluating small molecule effects on viral fusion protein conformational changes.
- Specific ligand sizes correlate with distinct modulation of the RBD activation pathway, offering insights for antiviral drug design.
- This approach allows for the assessment of reaction barriers on the nanosecond timescale, aiding in the development of novel therapeutics.
