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Extension of three-dimensional activity cliff information through systematic mapping of active analogs

机译：通过有效类似物的系统映射扩展三维活动悬崖信息

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摘要

Activity cliffs are formed by pairs or groups of structurally similar or analogous compounds with large potency differences against a given target. Three-dimensional activity cliffs (3D-cliffs) are obtained by comparison of the binding modes of ligands in complex X-ray structures. Currently, 630 high-confidence 3D-cliffs are available for a total of 61 human targets, which provide a knowledge base for structure-based SAR exploration and compound design. In this work, a systematic search for structural analogs of 3D-cliff compounds was carried out applying a variant of the matched molecular pair (MMP) formalism to further extend the structure-activity relationship (SAR) information associated with 3D-cliffs. In many instances, series of active analogs were successfully mapped to 3D-cliffs. Compound relationships were explored in network representations and key compounds involved in the formation of multiple 3D-cliffs and structural relationships identified. In addition, the superposition of analogs onto 3D-cliffs helped to rationalize distinguishing interactions and potency variations. In total, 1980 analogs were identified for 268 cliff compounds active against 50 human targets, which further extended 414 3D-cliffs and provided a variety of SAR environments for further study. A database comprising the currently available 3D-cliffs and assigned analogs has been generated and is freely available.
机译：活性悬崖通过对或组织性相似或类似化合物的组形成，具有较大效力差异对给定靶的效力差异。通过比较复合X射线结构中配体的结合模式来获得三维活性悬崖（3D悬崖）。目前，630个高信任3D悬崖可提供61个人的目标，为基于结构的SAR探索和复合设计提供了知识库。在这项工作中，对3D悬崖化合物的结构类似物的系统搜索进行施加匹配的分子对（MMP）形式主义的变体，以进一步延长与3D悬崖相关的结构 - 活性关系（SAR）信息。在许多情况下，成功映射到3D悬崖系列的活动模拟。在网络表示中探讨复合关系和涉及多个3D悬崖和结构关系的关键化合物。此外，模拟叠加到3D悬崖上有助于合理化相互作用和效力变化。总共鉴定了1980种类似物，用于对50个人靶标有效的268个悬崖化合物，其进一步延长了414个3D悬崖，并提供了各种SAR环境进行进一步研究。已生成包括当前可用的3D悬崖和分配类似物的数据库，并自由可用。

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  • 来源
    《RSC Advances》 |2015年第54期|共10页
  • 作者

    Hu Ye; Furtmann Norbert; Bajorath Juergen;

  • 作者单位

    Rhein Freidrich Wilhelms Univ Bonn LIMES Program Unit Chem Biol &

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

    Rhein Freidrich Wilhelms Univ Bonn LIMES Program Unit Chem Biol &

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

    Rhein Freidrich Wilhelms 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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