Informatics, Johnson & Johnson Pharmaceutical Research & Development, L.L.C. , Welsh & McKean Roads, Spring House, Pennsylvania 19477, United States.
J Chem Inf Model. 2011 May 23;51(5):1122-31. doi: 10.1021/ci200054u. Epub 2011 Apr 19.
We introduce Single R-Group Polymorphisms (SRPs, pronounced 'sharps'), an intuitive framework for analyzing substituent effects and activity cliffs in a single congeneric series. A SRP is a pair of compounds that differ only in a single R-group position. Because the same substituent pair may occur in multiple SRPs in the series (i.e., with different combinations of substituents at the other R-group positions), SRP analysis makes it easy to identify systematic substituent effects and activity cliffs at each point of variation (R-cliffs). SRPs can be visualized as a symmetric heatmap where each cell represents a particular pair of substituents color-coded by the average difference in activity between the compounds that contain that particular SRP. SRP maps offer several advantages over existing techniques for visualizing activity cliffs: 1) the chemical structures of all the substituents are displayed simultaneously on a single map, thus directly engaging the pattern recognition abilities of the medicinal chemist; 2) it is based on R-group decomposition, a natural paradigm for generating and rationalizing SAR; 3) it uses a heatmap representation that makes it easy to identify systematic trends in the data; 4) it generalizes the concept of activity cliffs beyond similarity by allowing the analyst to sort the substituents according to any property of interest or place them manually in any desired order.
我们引入了单 R 基团多态性（SRP，发音为“sharps”），这是一种用于在单一同类系列中分析取代基效应和活性悬崖的直观框架。SRP 是一对仅在单个 R 基团位置上有所不同的化合物。由于相同的取代基对可能在该系列中的多个 SRP 中出现（即在其他 R 基团位置上具有不同的取代基组合），因此 SRP 分析使得很容易在每个变化点（R 悬崖）识别系统的取代基效应和活性悬崖。SRP 可以可视化为对称热图，其中每个单元格代表一对特定的取代基，通过包含该特定 SRP 的化合物之间的活性差异的平均颜色编码。SRP 图谱相对于现有用于可视化活性悬崖的技术具有几个优势：1）所有取代基的化学结构同时显示在单个图谱上，从而直接利用药物化学家的模式识别能力；2）它基于 R 基团分解，这是生成和合理化 SAR 的自然范例；3）它使用热图表示形式，很容易识别数据中的系统趋势；4）它通过允许分析师根据任何感兴趣的属性对取代基进行排序或将其手动放置在所需的任何顺序中来扩展活性悬崖的概念，超越了相似性。
