AuthorㄩJiankun Lyu 1 2, Sheng Wang 3 4, Trent E Balius 1, Isha Singh 1, Anat Levit 1, Yurii S Moroz 5 6, Matthew J O'Meara 1, Tao Che 4, Enkhjargal Algaa 1, Kateryna Tolmachova 7, Andrey A Tolmachev 7, Brian K Shoichet 8, Bryan L Roth 9 10 11, John J Irwin
DOIㄩ10.1038/s41586-019-0917-9
JournalㄩNature. 2019 Feb;566(7743):224-229.
AbstractㄩDespite intense interest in expanding chemical space, libraries containing 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 that are otherwise unavailable. For each compound in the library, docking against AmpC 汕-lactamase (AmpC) and the D4 dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D4 dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D4 dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D4 dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D4 dopamine receptor.
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