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首页> 美国卫生研究院文献>Protein Science : A Publication of the Protein Society >The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzobthiophene derivatives: a binding mode for a structurally novel class of inhibitors.
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The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzobthiophene derivatives: a binding mode for a structurally novel class of inhibitors.

机译：与活性定点二氨基苯并b噻吩衍生物络合的人α-凝血酶的晶体结构：结构新颖的抑制剂类的结合方式。

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摘要

The crystal structures of four active site-directed thrombin inhibitors, 1-4, in a complex with human alpha-thrombin have been determined and refined at up to 2.0 A resolution using X-ray crystallography. These compounds belong to a structurally novel family of inhibitors based on a 2,3-disubstituted benzo[b]thiophene structure. Compared to traditional active-site directed inhibitors, the X-ray crystal structures of these complexes reveal a novel binding mode. Unexpectedly, the lipophilic benzo[b]thiophene nucleus of the inhibitor appears to bind in the S1 specificity pocket. At the same time, the basic amine of the C-3 side chain of the inhibitor interacts with the mostly hydrophobic proximal, S2, and distal, S3, binding sites. The second, basic amine side chain at C-2 was found to point away from the active site, occupying a location between the S1 and S1' sites. Together, the aromatic rings of the C-2 and C-3 side chains sandwich the indole ring of Trp60D contained in the thrombin S2 insertion loop defined by the sequence "Tyr-Pro-Pro-Trp." [The thrombin residue numbering used in this study is equivalent to that reported for chymotrypsinogen (Hartley BS, Shotton DM, 1971, The enzymes, vol. 3. New York: Academic Press. pp 323-373).] In contrast to the binding mode of more classical thrombin inhibitors (D-Phe-Pro-Arg-H, NAPAP, Argatroban), this novel class of benzo[b]thiophene derivatives does not engage in hydrogen bond formation with Gly216 of the thrombin active site. A detailed analysis of the three-dimensional structures not only provides a clearer understanding of the interaction of these agents with thrombin, but forms a foundation for rational structure-based drug design. The use of the data from this study has led to the design of derivatives that are up to 2,900-fold more potent than the screening hit 1.
机译：已经确定了四种活性定点凝血酶抑制剂1-4与人α凝血酶的复合物的晶体结构，并使用X射线晶体学对其进行了纯化，分辨率高达2.0A。这些化合物属于基于2，3-二取代的苯并[b]噻吩结构的新型抑制剂家族。与传统的活性部位定向抑制剂相比，这些配合物的X射线晶体结构揭示了一种新颖的结合模式。出乎意料的是，该抑制剂的亲脂性苯并[b]噻吩核似乎结合在S1特异性口袋中。同时，抑制剂的C-3侧链的碱性胺与大部分疏水的近端S2和远端S3结合位点相互作用。发现在C-2处的第二条碱性胺侧链指向远离活性位点的位置，位于S1和S1'位点之间。 C-2和C-3侧链的芳族环一起夹在凝血酶S2插入环中包含的Trp60D的吲哚环，序列“ Tyr-Pro-Pro-Trp”定义了该环。 [本研究中使用的凝血酶残基编号与胰凝乳蛋白酶原报道的编号相同（Hartley BS，Shotton DM，1971年，酶，第3卷，纽约：学术出版社，第323-373页）。]在更经典的凝血酶抑制剂（D-Phe-Pro-Arg-H，NAPAP，Argatroban）的模式中，这种新型的苯并[b]噻吩衍生物不会与凝血酶活性位点的Gly216形成氢键。对三维结构的详细分析不仅可以使人们更清楚地了解这些药物与凝血酶的相互作用，而且可以为基于合理结构的药物设计奠定基础。利用这项研究的数据，设计出比筛选命中率1高2900倍的衍生物。

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