Small molecules binding at any of the multiple regulatory sites on the molecular surface of a protein kinase may stabilize or disrupt the corresponding interaction, leading to consequent modulation of the kinase cellular activity. As such, each of these sites represents a potential drug target. Even targeting sites outside the immediate ATP site, the so-called exosites, may cause desirable biological effects through an allosteric mechanism. Targeting exosites can alleviate adverse effects and toxicity that is common when ATP-site compounds bind promiscuously to many other types of kinases. In this study we have identified, catalogued, and annotated all potentially druggable exosites on the protein kinase domains within the existing structural human kinome. We then priority-ranked these exosites by those most amenable to drug design. In order to identify pockets that are either consistent across the kinome, or unique and specific to a particular structure, we have also implemented a normalized representation of all pockets, and displayed these graphically. Finally, we have built a database and designed a web-based interface for users interested in accessing the 3-dimensional representations of these pockets. We envision this information will assist drug discovery efforts searching for untargeted binding pockets in the human kinome.

中文翻译：

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人类脚手袋的可药用外突。

结合在蛋白激酶分子表面上多个调控位点中的任何一个上的小分子可能会稳定或破坏相应的相互作用，从而导致对激酶细胞活性的调节。这样，这些位点中的每一个代表潜在的药物靶标。甚至靶向于紧邻ATP位置之外的位点（所谓的外生体），也可能通过变构机制引起理想的生物学效应。当ATP部位的化合物与许多其他类型的激酶混杂结合时，靶向外来剂可以减轻常见的不利影响和毒性。在这项研究中，我们已经识别，分类和注释了现有结构人kinome内蛋白激酶结构域上的所有潜在可药用外泌体。然后，我们按照最适合药物设计的优先顺序对这些异质石进行排序。为了识别在整个kinome上一致的口袋或特定于特定结构的口袋，我们还实现了所有口袋的标准化表示，并以图形方式显示了这些口袋。最后，我们建立了一个数据库，并为有兴趣访问这些口袋的3D表示形式的用户设计了一个基于Web的界面。我们预想，这些信息将有助于药物开发工作，以寻找人类kinome中未靶向的结合口袋。我们已经建立了一个数据库并设计了一个基于Web的界面，供有兴趣访问这些口袋的3D表示形式的用户使用。我们预想，这些信息将有助于药物开发工作，以寻找人类kinome中未靶向的结合口袋。我们已经建立了一个数据库并设计了一个基于Web的界面，供有兴趣访问这些口袋的3D表示形式的用户使用。我们预想，这些信息将有助于药物开发工作，以寻找人类kinome中未靶向的结合口袋。