Ultra-large library docking for discovering new chemotypes

Despite intense interest in expanding chemical space, libraries of hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here, we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds otherwise unavailable. The library was docked against AmpC β-lactamase and the D(4) dopamine receptor. From the top-ranking molecules, 44 and 549 were synthesized and tested, respectively. This revealed an unprecedented phenolate inhibitor of AmpC, which was optimized to 77 nM, the most potent non-covalent AmpC inhibitor known. Crystal structures of this and other new AmpC inhibitors confirmed the docking predictions. Against D(4), hit rates fell monotonically with docking score, and a hit-rate vs. score curve predicted 453,000 D(4) ligands in the library. Of 81 new chemotypes discovered, 30 were sub-micromolar, including a 180 pM sub-type selective agonist.