title: Discovery of diverse human dihydroorotate dehydrogenase inhibitors as immunosuppressive agents by structure-based virtual screening.
abstract: 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 IC(50) values ranging from 0.11 to 18.8 μM 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 IC(50) value of 0.11 μM. 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 (IC(50) = 1.78 μM) and presents a B-cell-specific profile with 17- and 26-fold selectivities toward T and Jurkat cells, respectively.
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Diao
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Lu
authors.forename: Huangtao
authors.initials: H
authors.lastname: Jin
authors.forename: Junsheng
authors.initials: J
authors.lastname: Zhu
authors.forename: Le
authors.initials: L
authors.lastname: Han
authors.forename: Minghao
authors.initials: M
authors.lastname: Xu
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Zhenjiang
authors.initials: Z
authors.lastname: Zhao
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Liu
authors.forename: Yufang
authors.initials: Y
authors.lastname: Xu
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D062126:Databases, Chemical; D000090722:Dihydroorotate Dehydrogenase; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D062105:Molecular Docking Simulation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000201:enzymology; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D044925:Oxidoreductases Acting on CH-CH Group Donors