von Matt A, Ehrhardt C, Burkhard P, Metternich R, Walkinshaw M, Tapparelli C
Novartis Pharma AG, Basel, Switzerland.
Bioorg Med Chem. 2000 Sep;8(9):2291-303. doi: 10.1016/s0968-0896(00)00147-4.
Based on the structural comparison of the S1 pocket in different trypsin-like serine proteases, a series of Boc-D-trimethylsilylalanine-proline-boro-X pinanediol derivatives, with boro-X being different amino boronic acids, have been synthesized as inhibitors of thrombin. Among the novel compounds, a number of derivatives were synthesized which appeared to have side-chain variants too big to fit into the S1 pocket. Nevertheless, these compounds inhibited thrombin in the nM range. The X-ray structure of one of these inhibitors bound to the active side of thrombin reveals that a new binding mode is responsible for these surprising results.
基于对不同胰蛋白酶样丝氨酸蛋白酶中S1口袋的结构比较，已合成了一系列Boc-D-三甲基硅烷基丙氨酸-脯氨酸-硼-X蒎烷二醇衍生物（其中硼-X为不同的氨基硼酸）作为凝血酶抑制剂。在这些新化合物中，合成了许多衍生物，其侧链变体似乎太大而无法装入S1口袋。然而，这些化合物在纳摩尔范围内抑制凝血酶。其中一种抑制剂与凝血酶活性位点结合的X射线结构表明，一种新的结合模式导致了这些惊人的结果。
