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晶体结构数据库中激酶铰链结合剂的支架挖掘

Scaffold mining of kinase hinge binders in crystal structure database.

作者信息

Xing Li, Rai Brajesh, Lunney Elizabeth A

机构信息

Pfizer Worldwide Research and Development, 200 CambridgePark Drive, Cambridge, MA, 02140, USA,

出版信息

J Comput Aided Mol Des. 2014 Jan;28(1):13-23. doi: 10.1007/s10822-013-9700-4. Epub 2013 Dec 29.

Abstract

Protein kinases are the second most prominent group of drug targets, after G-protein-coupled receptors. Despite their distinct inhibition mechanisms, the majority of kinase inhibitors engage the conserved hydrogen bond interactions with the backbone of hinge residues. We mined Pfizer internal crystal structure database (CSDb) comprising of several thousand of public as well as internal X-ray binary complexes to compile an inclusive list of hinge binding scaffolds. The minimum ring scaffolds with directly attached hetero-atoms and functional groups were extracted from the full compounds by applying a rule-based filtering procedure employing a comprehensive annotation of ATP-binding site of the human kinase complements. The results indicated large number of kinase inhibitors of diverse chemical structures are derived from a relatively small number of common scaffolds, which serve as the critical recognition elements for protein kinase interaction. Out of the nearly 4,000 kinase-inhibitor complexes in the CSDb we identified approximately 600 unique scaffolds. Hinge scaffolds are overwhelmingly flat with very little sp3 characteristics, and are less lipophilic than their corresponding parent compounds. Examples of the most common as well as the uncommon hinge scaffolds are presented. Although the most common scaffolds are found in complex with multiple kinase targets, a large number of them are uniquely bound to a specific kinase, suggesting certain scaffolds could be more promiscuous than the others. The compiled collection of hinge scaffolds along with their three-dimensional binding coordinates could serve as basis set for hinge hopping, a practice frequently employed to generate novel invention as well as to optimize existing leads in medicinal chemistry.

摘要

蛋白激酶是仅次于G蛋白偶联受体的第二大突出的药物靶点类别。尽管激酶抑制剂具有不同的抑制机制,但大多数激酶抑制剂都与铰链残基的主链形成保守的氢键相互作用。我们挖掘了辉瑞公司的内部晶体结构数据库(CSDb),该数据库包含数千个公开的以及内部的X射线二元复合物,以编制一份全面的铰链结合支架列表。通过应用基于规则的过滤程序,利用人类激酶互补体ATP结合位点的全面注释,从完整化合物中提取具有直接连接杂原子和官能团的最小环支架。结果表明,大量化学结构多样的激酶抑制剂源自相对较少的常见支架,这些支架是蛋白激酶相互作用的关键识别元件。在CSDb中近4000个激酶抑制剂复合物中,我们鉴定出约600个独特的支架。铰链支架绝大多数是扁平的,几乎没有sp3特征,并且比它们相应的母体化合物亲脂性更低。文中给出了最常见以及不常见的铰链支架的例子。尽管最常见的支架与多个激酶靶点形成复合物,但其中许多仅与特定激酶结合,这表明某些支架可能比其他支架更具 promiscuous性。汇编的铰链支架集合及其三维结合坐标可作为铰链跳跃的基础集,铰链跳跃是药物化学中经常用于产生新发明以及优化现有先导化合物的一种做法。

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