Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, D-53113 Bonn, Germany.
Future Med Chem. 2011 Mar;3(4):425-36. doi: 10.4155/fmc.10.293.
Bioisosteric replacements are commonly understood to be replacements of groups of atoms in bioactive compounds that retain their specific activity and retain, or further improve, compound potency. Such chemical modifications are of high interest in medicinal chemistry and are often considered in compound exploration and optimization.
We have applied the matched molecular pair formalism to carry out a large-scale data mining study to identify bioisosteres in publicly available active compounds with similar potency. Our data mining effort has identified a set of 96 nonredundant bioisosteric replacements, approximately half of which were previously unobserved. However, a number of replacements commonly considered to be bioisosteric did not meet our extended bioisostere selection criteria, which included high frequency of occurrence, limited potency alterations and activity across different target families. Furthermore, many commonly known bioisosteric replacements were found to be dependent on the structural context in which they occurred.
The systematic analysis of public domain compound data presented herein provides an alternative route to the identification of bioisosteric replacements and further extends the spectrum of currently known bioisosteres. We provide a compendium of bioisosteric replacements that are well supported by currently available compound data.
生物等排体替换通常被理解为在具有特定活性的生物活性化合物中替换原子团，同时保留或进一步提高化合物的效力。这种化学修饰在药物化学中非常重要，并且经常在化合物的探索和优化中被考虑。
我们应用匹配分子对形式来进行大规模的数据挖掘研究，以识别具有相似效力的公开可用活性化合物中的生物等排体。我们的数据挖掘工作已经确定了一组 96 个非冗余的生物等排体替换，其中大约一半是以前未观察到的。然而，一些通常被认为是生物等排体的替换不符合我们扩展的生物等排体选择标准，这些标准包括高出现频率、有限的效力改变和在不同靶家族中的活性。此外，许多常见的已知生物等排体替换被发现依赖于它们发生的结构上下文。
本文对公共领域化合物数据的系统分析提供了一种识别生物等排体替换的替代方法，并进一步扩展了当前已知生物等排体的范围。我们提供了一组有充分现有化合物数据支持的生物等排体替换。
