文献类型：期刊文献

英文题名：Discovery of Diverse Human Dihydroorotate Dehydrogenase Inhibitors as Immunosuppressive Agents by Structure-Based Virtual Screening

作者：Diao, Yanyan[1];Lu, Weiqiang[1];Jin, Huangtao[1];Zhu, Junsheng[1];Han, Le[1];Xu, Minghao[1];Gao, Rui[1];Shen, Xu[1];Zhao, Zhenjiang[1];Liu, Xiaofeng[1];Xu, Yufang[1];Huang, Jin[1];Li, Honglin[1]

机构：[1]E China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai Key Lab Chem Biol,Sch Pharm, Shanghai 200237, Peoples R China

年份：2012

卷号：55

期号：19

起止页码：8341

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000309643500013)】；

基金：This work was supported by the Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China (grants 21173076, 81102375, 10979072, 81222046, and 81230076), the Specialized Research Fund for the Doctoral Program of Higher Education of China (grants 20090074120012 and 20110074120009), the Special Fund for Major State Basic Research Project (grant 2009CB918501), the Shanghai Committee of Science and Technology (grants 11DZ2260600 and 10431902600), and the 863 Hi-Tech Program of China (grant 2012AA020308). Honglin Li is also sponsored by Program for New Century Excellent Talents in University (grant NCET-10-0378).

语种：英文

摘要：This study applied an efficient virtual screening strategy integrating molecular docking with MM-GBSA rescoring to identify diverse human dihydroorotate dehydrogenase (hDHODH) inhibitors. Eighteen compounds with IC50 values ranging from 0.11 to 18.8 mu M were identified as novel hDHODH inhibitors that exhibited overall species-selectivity over Plasmodium falciparum dihydroorotate dehydrogenase (pfDHODH). Compound 8, the most potent one, showed low micromolar inhibitory activity against hDHODH with an IC50 value of 0.11 mu M. Moreover, lipopolysaccharide-induced B-cell assay and mixed lymphocyte reaction assay revealed that most of the hits showed potent antiproliferative activity against B and T cells, which demonstrates their potential application as immunosuppressive agents. In particular, compound 18 exhibited potent B-cell inhibitory activity (IC50 = 1.78 mu M) and presents a B-cell-specific profile with 17- and 26-fold selectivities toward T and Jurkat cells, respectively.