Exploring Activity Cliffs in Medicinal Chemistry Miniperspective
Exploring Activity Cliffs in Medicinal Chemistry Miniperspective
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DOI：
10.1021/jm201706b
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发表时间：
2012-04-12
影响因子：
7.3
通讯作者：
Bajorath, Juergen
中科院分区：
文献类型：
--
作者：
Stumpfe, Dagmar;Bajorath, Juergen
近年来，结构-活动关系（SAR）越来越多地通过挖掘大型复合数据集进行研究，导致活动景观概念的复兴。1− 5一般来说，活性景观被定义为任何整合了共享特定活性的化合物之间的相似性和效力关系的图形表示。5从不同设计的活动景观表示中，可以提取复合数据集中存在的全球和局部SAR特征。3，5大规模SAR分析是对经典定量构效关系（QSAR）建模的补充。6例如，活动景观模型使得有可能描绘出SAR连续性区域，在这些区域，化合物结构的逐渐变化导致化合物效力的适度变化。SAR连续性的存在为QSAR分析和由此产生的化合物活性预测提供了基本基础。6此外，活性景观还揭示了SAR不连续的区域，其中化学结构的微小变化导致化合物效力的巨大变化，这是铅优化中经常遇到的情况。然而，SAR不连续性的存在福尔斯落在QSAR范例的适用范围之外。7然而，通常认为活性景观中SAR不连续的区域提供了大量SAR信息5，8，因为活性化合物的小结构变化会导致大的效力效应。SAR不连续性的最突出形式是自20世纪90年代初以来在药物化学相关科学文献中讨论的活性悬崖5、7、8。一般来说，活性悬崖被定义为一对结构相似或类似的化合物，但效力差异很大。5，7作为SAR不连续性的一种极端形式，活动悬崖代表了活动景观的最突出特征，并且通常是其分析的主要焦点。
In recent years, structure− activity relationships (SARs) have increasingly been studied through mining of large compound data sets, leading to a renaissance of the activity landscape concept. 1− 5 In general terms, an activity landscape is defined as any graphical representation that integrates similarity and potency relationships between compounds sharing a specific activity. 5 From activity landscape representations of different design, both global and local SAR features present in compound data sets can be extracted. 3, 5 Large-scale SAR analysis complements classical quantitative structure− activity relationship (QSAR) modeling. 6 For example, activity landscape models make it possible to delineate regions of SAR continuity where gradual changes in compound structure lead to moderate changes in compound potency. The presence of SAR continuity provides a fundamental basis for QSAR analysis and resulting compound activity predictions. 6 Furthermore, activity landscapes also reveal regions of SAR discontinuity where small changes in chemical structure lead to large changes in compound potency, a scenario often encountered in lead optimization. However, the presence of SAR discontinuity falls outside the applicability domain of the QSAR paradigm. 7 However, regions of SAR discontinuity in activity landscapes are generally thought to provide much SAR information 5, 8 because small structural changes of active compounds lead to large potency effects. The most prominent form of SAR discontinuity is provided by activity cliffs 5, 7, 8 that have been discussed in the medicinal chemistry relevant scientific literature since the early 1990s. 9 In general, an activity cliff is defined as a pair of structurally similar or analogous compounds having a large difference in potency. 5, 7 As an extreme form of SAR discontinuity, activity cliffs represent the most prominent features of activity landscapes and are often the primary focal point of their analysis.