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首页> 外文期刊>Acta crystallographica.Section D. Biological crystallography >Structure of thrombin complexed with selective non-electrophilic inhibitors having cyclohexyl moieties at P1
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Structure of thrombin complexed with selective non-electrophilic inhibitors having cyclohexyl moieties at P1

机译：凝血酶的结构和选择性non-electrophilic抑制剂有环己基在P1半个

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The crystal structures of five new non-electrophilic β-strand-templated thrombin active-site inhibitors have been determined bound to the enzyme. Four co-crystallize with hirugen and inhibitor isomorphously to produce thrombin-hirugen crystals (monoclinic, space group C2), while one co-crystallizes in the hexagonal system, space group P6_5. A 1,4-substituted cyclohexyl moiety is conserved at the P1 position of all the inhibitors, along with a fused hetero-bicyclic five- and six-membered ring that occupies the P2 site. Amino, amidino and aminoimidazole groups are attached to the cyclohexyl ring for recognition at the S1 specificity site, while benzylsul-fonyl and diphenyl groups enhance the binding at the S3 subsite. The cyclohexyl groups at the P1 positions of three of the inhibitors appear to be in the energetically favored chair conformation, while the imidazole-substituted cyclohexyl rings are in a boat conformation. Somewhat unexpectedly, the two cyclohexyl-aminoimidazole groups bind differently in the specificity site; the unique binding of one is heretofore unreported. The other inhibitors generally mimic arginyl binding at S1. This group of inhibitors combines the non-electrophilicity and selectivity of DAPA-like compounds and the more optimal binding features of the S1-S3 sites of thrombin for peptidic molecules, which results in highly potent (binding constants 12 nM-16pM, one being 1.1μM) and selective (ranging from 140 to 20 000 times more selective compared with trypsin) inhibitors of thrombin. The binding modes of these novel inhibitors are correlated with their binding constants, as is their selectivity, in order to provide further insight for the design of therapeutic antithrombotic agents that inhibit thrombin directly at the active site.
机译：五个新晶体结构non-electrophilicβ-strand-templated凝血酶活性位点抑制剂已被确定的酶。生产和抑制剂同形thrombin-hirugen晶体(单斜、空间集团C2),而co-crystallizes之一六角晶系,空间群P6_5。1, 4-substituted环己基一半是守恒的P1位置的抑制剂,以及融合hetero-bicyclic五和六元环,占据了P2的网站。和aminoimidazole组上环己基环的识别S1特异性的网站,而benzylsul-fonyl和二苯组增强S3的绑定子站。的位置的三个似乎抑制剂在大力支持椅式构象,虽然imidazole-substituted环己基环船式构象。出乎意料,两个cyclohexyl-aminoimidazole组绑定不同的特异性网站;独特的绑定一个是迄今为止报道。在S1 arginyl绑定。结合了non-electrophilicity和选择性DAPA-like化合物和更优的绑定S1-S3网站的凝血酶的特点peptidic分子,结果在高度强有力的(12 nM-16pM绑定常量,一个1.1μM)和选择性(从140到000倍的选择性与胰蛋白酶)凝血酶的抑制剂。这些小说抑制剂与他们有关绑定常量,是他们的选择,为了进一步了解设计抑制的抗血栓形成的药物治疗直接凝血酶的活性部位。

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