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Updated: Jun 12, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

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 York 10065, United States.

Journal of Chemical Information and Modeling

|June 11, 2026

Summary

This summary is machine-generated.

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.

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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.