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.
J Med Chem. 2012 Oct 11;55(19):8341-9. doi: 10.1021/jm300630p. Epub 2012 Sep 28.
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.
本研究应用了一种有效的虚拟筛选策略，将分子对接与 MM-GBSA 再评分相结合，以鉴定多种人二氢乳清酸脱氢酶（hDHODH）抑制剂。鉴定出 18 种化合物，其 IC50值范围为 0.11 至 18.8 μM，它们是新型 hDHODH 抑制剂，对恶性疟原虫二氢乳清酸脱氢酶（pfDHODH）具有总体物种选择性。化合物 8 是最有效的化合物，对 hDHODH 表现出低微摩尔抑制活性，IC50值为 0.11 μM。此外，脂多糖诱导的 B 细胞测定和混合淋巴细胞反应测定表明，大多数化合物对 B 和 T 细胞表现出很强的增殖抑制活性，这表明它们有作为免疫抑制剂的应用潜力。特别是，化合物 18 表现出很强的 B 细胞抑制活性（IC50值为 1.78 μM），并具有 B 细胞特异性特征，对 T 细胞和 Jurkat 细胞的选择性分别为 17 倍和 26 倍。
