Druggable exosites of the human kino-pocketome.
Druggable exosites of the human kino-pocketome.
复制标题
人类动袋组的可药物外位点。
DOI：
10.1007/s10822-019-00276-y
复制
发表时间：
2020
影响因子：
3.5
通讯作者：
Abagyan,Ruben
中科院分区：
文献类型：
--
作者：
Nicola,George;Kufareva,Irina;Ilatovskiy,AndreyV;Abagyan,Ruben
在蛋白激酶的分子表面上的多个调节位点中的任何一个处结合的小分子可以稳定或破坏相应的相互作用，从而导致激酶细胞活性的随后调节。因此，这些位点中的每一个都代表了潜在的药物靶标。即使是直接ATP位点之外的靶向位点，所谓的dexosite，也可能通过变构机制引起期望的生物学效应。靶向外部位点可以减轻当ATP位点化合物混杂地与许多其他类型的激酶结合时常见的副作用和毒性。在这项研究中，我们已经确定，编目，并注释了所有潜在的可药用的exosites的蛋白激酶结构域内现有的结构人类激酶组。然后，我们将这些外部位点按最适合药物设计的那些进行优先级排序。为了识别在激酶组中一致或对特定结构独特和特异的口袋，我们还实现了所有口袋的归一化表示，并以图形方式显示这些口袋。最后，我们建立了一个数据库并为有兴趣访问这些口袋的三维表示的用户设计了一个基于网络的界面。我们设想这些信息将有助于药物发现工作，寻找人类激酶组中的非靶向结合口袋。
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-calledexosites,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.