文献类型：期刊文献

英文题名：Ultra-large library docking for discovering new chemotypes

作者：Lyu, Jiankun[1,2];Wang, Sheng[3,4];Balius, Trent E.[1];Singh, Isha[1];Levit, Anat[1];Moroz, Yurii S.[5,6];O'Meara, Matthew J.[1];Che, Tao[4];Algaa, Enkhjargal[1];Tolmachova, Kateryna[7];Tolmachev, Andrey A.[7];Shoichet, Brian K.[1];Roth, Bryan L.[4,8,9];Irwin, John J.[1]

机构：[1]Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94115 USA;[2]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[3]Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, State Key Lab Mol Biol,CAS Ctr Excellence Mol Cel, Shanghai, Peoples R China;[4]Univ North Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27515 USA;[5]Natl Taras Shevchenko Univ Kiev, Kiev, Ukraine;[6]Chemspace, Riga, Latvia;[7]Enamine, Kiev, Ukraine;[8]Univ North Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27515 USA;[9]Univ North Carolina, Sch Med, NIMH PDSP, Chapel Hill, NC 27515 USA

年份：2019

卷号：566

期号：7743

起止页码：224

外文期刊名：NATURE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000458503900042)】；

基金：This research was supported by GM71896 (to J.J.I.); R35 GM122481 and a UCSF PBBR New Frontier Award (to B.K.S.); R01 MH112205, U24DK1169195 and the NIMH Psychoactive Drug Screening Contract (to B.L.R.); Strategic Priority Research Program of the Chinese Academy of Sciences, grant number XDB19000000 (to S.W.). We thank R. Stein and I. Fish for help with AmpC preparation, H. Torosyan for aggregation assays, R. H. J. Olsen for developing the D4 receptor BRET assay, B. Wong and C. Dandarchuluun for computer support, and M. Korczynska and J. Pottel for reading this manuscript; ChemAxon for a license to JChem, OpenEye Scientific software for a license to OEChem and Omega2, Molecular Networks for a license to Corina, and Molinspriation for a license to Mitools.

语种：英文

摘要：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.