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Identification and analysis of the currently available high-confidence three-dimensional activity cliffs

机译：目前可用的高信心三维活动悬崖的识别和分析

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摘要

Three-dimensional activity cliffs (3D-cliffs) were determined on the basis of the X-ray structures of protein-ligand complexes currently available in the Protein Data Bank (PDB). For a given target, all the bound small molecular ligands were compared in a pairwise manner and ligand pairs with at least 80% 3D similarity of their binding modes and an at least 100-fold difference in potency were identified and classified as 3D-cliffs. Only high-confidence activity data were considered. All the 3D-cliffs were subjected to visual inspection and categorized according to ligand-target interaction differences. In addition, relationships between 3D-cliffs were systematically explored. Compared to a previous survey, in which 216 3D-cliffs were detected, the current study identified a total of 630 3D-cliffs that involved 580 unique ligands with activity against 61 human targets belonging to 25 families. Thus, over the past few years, there has been significant growth in high-confidence activity cliff information at the structural level. Notable increases in the number of 3D-cliffs were observed for a number of different targets, in particular, proteases. The pool of currently available 3D-cliffs provides a rich source of information for structure-activity relationship (SAR) analysis and structure-based design.
机译：基于蛋白质数据库（PDB）目前可用的蛋白质 - 配体复合物的X射线结构确定三维活性悬崖（3D悬崖）。对于给定的靶，将所有结合的小分子配体以成对的方式进行比较，并且具有至少80％的它们的结合模式的3D相似性的配体对和效力至少100倍的差异被鉴定并归类为3D悬崖。只考虑了高信心活动数据。所有3D悬崖都经受视觉检查并根据配体 - 目标相互作用差异进行分类。此外，系统地探索了3D悬崖之间的关系。与先前的调查相比，检测到216 316悬崖，目前的研究共鉴定了总共630个3D悬崖，涉及580个独特的配体，其活动与属于25个家庭的61名人类目标。因此，在过去几年中，结构层面的高置信活动悬崖信息存在显着增长。对于许多不同的靶标，观察到3D悬崖数量的显着增加，特别是蛋白酶。目前可用的3D悬崖池提供了丰富的结构 - 活动关系（SAR）分析和基于结构的设计来源。

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  • 来源
    《RSC Advances》 |2015年第54期|共9页
  • 作者

    Furtmann Norbert; Hu Ye; Guetschow Michael; Bajorath Juergen;

  • 作者单位

    Univ Bonn LIMES Program Unit Chem Biol &

    Med Chem Dept Life Sci Informat B IT D-53113 Bonn Germany;

    Univ Bonn LIMES Program Unit Chem Biol &

    Med Chem Dept Life Sci Informat B IT D-53113 Bonn Germany;

    Univ Bonn Inst Pharmaceut D-53121 Bonn Germany;

    Univ Bonn LIMES Program Unit Chem Biol &

    Med Chem Dept Life Sci Informat B IT D-53113 Bonn Germany;

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  • 正文语种 eng
  • 中图分类 化学;
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