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Updated: Jun 12, 2026
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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
AI-Enforced Ultra-Large Virtual Screening Discovers Potent CD28 Binders
Saurabh Upadhyay1, Michele Roggia2, Shaoren Yuan1
1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York10065, United States.
Journal of Chemical Information and Modeling
|June 11, 2026
Summary
This study introduces PyRMD2Dock, an AI-driven platform for structure-based virtual screening. It successfully identified novel small molecules targeting the immune receptor CD28, demonstrating potent disruption and functional blockade.
Area of Science:
- Drug Discovery
- Computational Chemistry
- Immunology
Background:
- Targeting protein-protein interactions (PPIs) with small molecules is difficult due to challenging binding sites.
- Traditional structure-based virtual screening (SBVS) faces computational limitations with vast chemical libraries.
Purpose of the Study:
- To apply the AI-driven PyRMD2Dock platform for prospective, real-world identification of small-molecule modulators for the immune receptor CD28.
- To overcome computational bottlenecks in screening ultralarge chemical spaces for novel chemotypes.
Main Methods:
- AI-enforced SBVS workflow integrating machine learning and standard docking (PyRMD2Dock).
- Docking of 2.4 million molecules into CD28, followed by training classification models.
- Rapid screening of ~46 million additional compounds using optimized models, followed by filtering and clustering.
Main Results:
- Identification of 232 highly prioritized ligands, with a strong hit rate upon experimental validation.
- Discovery of lead compounds (100 and 104) with submicromolar affinity for CD28.
- Demonstrated potent CD28-CD80 disruption, functional blockade in cellular assays, and reduced cytokine secretion in co-culture models.
Conclusions:
- PyRMD2Dock is a validated, scalable, and effective platform for discovering small-molecule modulators of challenging immune receptor interfaces.
- The identified compounds represent promising leads for therapeutic intervention in immune-related diseases.
