Changing the HTS Paradigm: AI-Driven Iterative Screening for Hit Finding

Abstract

Iterative screening is a process in which screening is done in batches, with each batch filled by using machine learning to select the most promising compounds from the library based on the previous results. We believe iterative screening is poised to enhance the screening process by improving hit finding while at the same time reducing the number of compounds screened. In addition, we see this process as a key enabler of next-generation high-throughput screening (HTS), which uses more complex assays that better describe the biology but demand more resource per screened compound. To demonstrate the utility of these methods, we retrospectively analyze HTS data from PubChem with a focus on machine learning–based screening strategies that can be readily implemented in practice. Our results show that over a variety of HTS experimental paradigms, an iterative screening setup that screens a total of 35% of the screening collection over as few as three iterations has a median return rate of approximately 70% of the active compounds. Increasing the portion of the library screened to 50% yields median returns of approximately 80% of actives. Using six iterations increases these return rates to 78% and 90%, respectively. The best results were achieved with machine learning models that can be run on a standard desktop. By demonstrating that the utility of iterative screening holds true even with a small number of iterations, and without requiring significant computational resources, we provide a roadmap for the practical implementation of these techniques in hit finding.