Machine learning assisted hit prioritization for high throughput screening in drug discovery

05 December 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Efficient prioritization of bioactive compounds from high throughput screening campaigns is a fundamental challenge for accelerating drug development efforts. In this study, we present the first data-driven approach to simultaneously detect assay interferents and prioritize true bioactive compounds. By analyzing the learning dynamics during training of a gradient boosting model on noisy high throughput screening data using a novel formulation of sample influence, we are able to distinguish between compounds exhibiting the desired biological response and the ones producing assay artifacts. Therefore, our method enables false positive and true positive detection without relying on prior screens or assay interference mechanisms, making it applicable to any high throughput screening campaign. We demonstrate that our approach consistently excludes assay interferents with different mechanisms and prioritizes biologically relevant compounds more efficiently than all tested baselines, including a retrospective case study simulating its use in a real drug discovery campaign. Finally, our tool is extremely computationally efficient, requiring less than 30 seconds per assay on low-resource hardware. As such, our findings show that our method is an ideal addition to existing false positive detection tools and can be used to guide further pharmacological optimization after high throughput screening campaigns.


High throughput screening
Gradient boosting
Sample influence

Supplementary materials

Supporting information
The Supporting Information contains a technical explanation of the theoretical aspects of MVS-A, the Methods section detailing how each approach was implemented, training time measurements, chemical space diversity analysis, false positive identification performance for the alternative machine-learning approaches, overlap analysis between the predictions of MVS-A and alternative machine-learning approaches.


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