Ultra-large library docking for discovering new chemotypes

Jiankun Lyu, Sheng Wang, Trent E. Balius, Isha Singh, Anat Levit, Yurii S. Moroz, Matthew J. O’Meara, Tao Che, Enkhjargal Algaa, Kateryna Tolmachova, Andrey A. Tolmachev, Brian K. Shoichet (), Bryan L. Roth () and John J. Irwin ()
Additional contact information
Jiankun Lyu: University of California, San Francisco
Sheng Wang: University of Chinese Academy of Sciences
Trent E. Balius: University of California, San Francisco
Isha Singh: University of California, San Francisco
Anat Levit: University of California, San Francisco
Yurii S. Moroz: National Taras Shevchenko University of Kiev
Matthew J. O’Meara: University of California, San Francisco
Tao Che: University of North Carolina at Chapel Hill School of Medicine
Enkhjargal Algaa: University of California, San Francisco
Kateryna Tolmachova: Enamine
Andrey A. Tolmachev: Enamine
Brian K. Shoichet: University of California, San Francisco
Bryan L. Roth: University of North Carolina at Chapel Hill School of Medicine
John J. Irwin: University of California, San Francisco

Nature, 2019, vol. 566, issue 7743, 224-229

Abstract: Abstract Despite 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 β-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.

Date: 2019
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DOI: 10.1038/s41586-019-0917-9

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