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Published on: March 3, 2015
HTS-Oracle v2: Prospective Ai-Guided Discovery and Experimental Validation of Small Molecule Modulators Across
Somaya A Abdel-Rahman1, Moustafa T Gabr1
1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York10065, United States.
Journal of Chemical Information and Modeling
|July 13, 2026
Summary
HTS-Oracle v2 significantly improves small molecule discovery for immunotherapy targets. This AI platform achieves high validated hit rates, reducing screening burden and accelerating drug development.
Area of Science:
- Drug Discovery
- Computational Chemistry
- Immunotherapy
Background:
- High-throughput screening (HTS) is crucial for small molecule discovery but underperforms for immunotherapy targets.
- Validated hit rates in HTS for immunotherapy targets are consistently below 0.1%.
Purpose of the Study:
- Introduce HTS-Oracle v2, an enhanced AI platform for improved hit discovery in early-phase drug development.
- Ensure honest performance estimates through rigorous cross-validation.
Main Methods:
- Trained and validated HTS-Oracle v2 on four immune checkpoint targets (CD28, ICOS, LAG-3, TIGIT).
- Employed rigorous cross-validation to assess model performance.
- Applied HTS-Oracle v2 to screen an 8960-compound library, selecting 25 compounds per target for validation using temperature-related intensity change (TRIC) technology.
Main Results:
- Achieved high ROC-AUC values under cross-validation: 0.968 (CD28), 0.969 (ICOS), 0.875 (LAG-3), and 0.928 (TIGIT).
- Prospectively identified validated hit rates of 16-24% from 25 selected compounds per target.
- Captured 67-80% of all experimentally confirmed hits within the 25 prospectively selected compounds per target.
Conclusions:
- HTS-Oracle v2 demonstrates exceptional efficiency and accuracy for AI-guided hit discovery against immunotherapy targets.
- The platform significantly reduces screening burden while increasing validated hit rates.
- HTS-Oracle v2 represents a powerful tool for accelerating the discovery of novel immunotherapies.
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