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

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• 作者：Yanyan Diao ; Weiqiang Lu ; Huangtao Jin ; Junsheng Zhu ; Le Han ; Minghao Xu ; Rui Gao ; Xu Shen ; Zhenjiang Zhao ; Xiaofeng Liu ; Yufang Xu ; Jin Huang ; Honglin Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8341-8349
• 全文大小：475K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

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 渭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 渭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 渭M) and presents a B-cell-specific profile with 17- and 26-fold selectivities toward T and Jurkat cells, respectively.