期刊
NATURE
卷 566, 期 7743, 页码 224-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-019-0917-9
关键词
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资金
- UCSF PBBR New Frontier Award
- NIMH Psychoactive Drug Screening Contract
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB19000000]
- [GM71896]
- [R35 GM122481]
- [R01 MH112205]
- [U24DK1169195]
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 beta-lactamase (AmpC) and the D-4 dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D-4 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 D-4 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 D-4 dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D-4 dopamine receptor.
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