AI-Powered Virtual Screening of Large Compound Libraries Leads to the Discovery of Novel Inhibitors of Sirtuin-1.

The discovery of new scaffolds and chemotypes via high-throughput screening is tedious and resource intensive. Yet, there are millions of small molecules commercially available, rendering comprehensive in vitro tests intractable. We show how smart algorithms reduce large screening collections to target-specific sets of just a few hundred small molecules, allowing for a much faster and more cost-effective hit discovery process. We showcase the application of this virtual screening strategy by preselecting 434 compounds for Sirtuin-1 inhibition from a library of 2.6 million compounds, corresponding to 0.02% of the original library. Multistage in vitro validation ultimately confirmed nine chemically novel inhibitors. When compared to a competitive benchmark study for Sirtuin-1, our method shows a 12-fold higher hit rate. The results demonstrate how AI-driven preselection from large screening libraries allows for a massive reduction in the number of small molecules to be tested in vitro while still retaining a large number of hits.