Baumgartner Roland, Walloschek Markus, Kralik Martin, Gotschlich Astrid, Tasler Stefan, Mies Jan, Leban Johann
4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.
J Med Chem. 2006 Feb 23;49(4):1239-47. doi: 10.1021/jm0506975.
Human dihydroorotate dehydrogenase (DHODH) represents an important target for the treatment of hyperproliferative and inflammatory diseases. In the cell DHODH catalyzes the rate-limiting step of the de novo pyrimidine biosynthesis. DHODH inhibition results in beneficial immunosuppressant and antiproliferative effects in diseases such as rheumatoid arthritis. Here, we present high-resolution X-ray structures of human DHODH in complex with a novel class of low molecular weight compounds that inhibit the enzyme in the nanomolar range. Some compounds showed an interesting dual binding mode within the same cocrystal strongly depending on the nature of chemical substitution. Measured in vitro activity data correlated with the prevailing mode of binding and explained the observed structure-activity relationship. Additionally, the X-ray data confirmed the competitive nature of the inhibitors toward the putative ubiquinone binding site and will guide structure-based design and synthesis of molecules with higher activity.
人二氢乳清酸脱氢酶（DHODH）是治疗过度增殖性疾病和炎症性疾病的重要靶点。在细胞中，DHODH催化从头嘧啶生物合成的限速步骤。在类风湿性关节炎等疾病中，抑制DHODH会产生有益的免疫抑制和抗增殖作用。在此，我们展示了人DHODH与一类新型低分子量化合物形成复合物的高分辨率X射线结构，这类化合物在纳摩尔范围内抑制该酶。一些化合物在同一共晶体中表现出有趣的双重结合模式，这很大程度上取决于化学取代的性质。体外活性数据与主要结合模式相关，并解释了观察到的构效关系。此外，X射线数据证实了抑制剂对假定的泛醌结合位点的竞争性，并将指导基于结构的设计和合成具有更高活性的分子。
