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Novel method to identify group-specific non-catalytic pockets of human kinome for drug design

机译：用于鉴定药物设计的人体Kinome群特异性非催化口袋的新方法

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Kinase proteins have been intensively investigated as drug targets for decades because of their crucial involvement in many biological pathways. Most kinase drugs target the catalytic ATP pocket, which is highly conserved across the kinome, and as such often leads to potential side effects. It is thus highly desirable to develop non-ATP-competitive drugs that inhibit kinase activity via allosteric interactions. However, to elucidate the complex allosteric mechanism, it is essential to build a novel method to characterize a comprehensive non-catalytic pocket for the structurally well-covered human kinome. In this work, we developed a hybrid approach of sequence, structure and network analysis on 168 representative kinases to identify group-specific non-catalytic pockets. The geometric analysis was performed to cluster these pockets and to identify group-specific non-catalytic pockets based on their shape and location characteristics. Subsequent sequence evolutionary analysis reveals the crucial residues of each pocket that will likely interact with inhibitors binding to the pocket. These residues thus serve as potential biomarkers of each pocket for inhibitor design. Moreover, the residue–residue interaction network analysis was performed to elucidate the complex allosteric mechanism of these non-catalytic pockets. The final list of 14 group-specific non-catalytic pockets and their characterized structural, sequence and network features can be an enabling dataset for drug design effort at the human kinome level. The developed hybrid approach is able to identify group-specific non-catalytic pockets and will benefit the research related to human kinome drug design.
机译：由于它们在许多生物途径中的关键受累，这几十年来，激酶蛋白被密集地调查了药物目标。大多数激酶药物靶向催化ATP口袋，其在kinome上高度保守，因此通常导致潜在的副作用。因此，非常希望开发非ATP竞争性药物通过变构相互作用抑制激酶活性。然而，为了阐明复杂的变形机制，必须建立一种新的方法，以表征在结构良好的人类肺组合中的综合非催化口袋。在这项工作中，我们在168个代表性激酶上开发了一种序列，结构和网络分析的混合方法，以鉴定群体特异性的非催化口袋。进行几何分析以基于其形状和位置特性簇形成这些凹穴并鉴定组特异性非催化袋。随后的序列进化分析揭示了每个口袋的关键残留物，其可能与抑制剂相互作用，抑制剂与袋粘合。因此，这些残留物用作每个口袋的潜在生物标志物，用于抑制剂设计。此外，进行残余物 - 残基相互作用网络分析以阐明这些非催化袋的复杂体变性机理。最终列表14个特定于组的非催化口袋及其表征的结构，序列和网络特征可以是人类Kinome水平的药物设计努力的支持数据集。开发的杂种方法能够鉴定特定于群体的非催化口袋，并将有益于与人类肺组合药物设计有关的研究。

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