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Nature. 2019 Feb;566(7743):224-229. doi: 10.1038/s41586-019-0917-9. Epub 2019 Feb 6.

Ultra-large library docking for discovering new chemotypes.

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
2
State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai, China.
3
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
4
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
5
National Taras Shevchenko University of Kiev, Kiev, Ukraine.
6
Chemspace, Riga, Latvia.
7
Enamine, Kiev, Ukraine.
8
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA. bshoichet@gmail.com.
9
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
10
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
11
National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
12
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA. jir322@gmail.com.

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.

PMID:
30728502
PMCID:
PMC6383769
[Available on 2019-08-06]
DOI:
10.1038/s41586-019-0917-9

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