Tanikawa Tetsuya, Fridman Micha, Zhu Wenjiang, Faulk Brian, Joseph Isaac C, Kahne Daniel, Wagner Bridget K, Clemons Paul A
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
J Am Chem Soc. 2009 Apr 15;131(14):5075-83. doi: 10.1021/ja806583y.
Designing better small-molecule discovery libraries requires having methods to assess the consequences of different synthesis decisions on the biological performance of resulting library members. Since we are particularly interested in how stereochemistry affects performance in biological assays, we prepared a disaccharide library containing systematic stereochemical variations, assayed the library for different biological effects, and developed methods to assess the similarity of performance between members across multiple assays. These methods allow us to ask which subsets of stereochemical features best predict similarity in patterns of biological performance between individual members and which features produce the greatest variation of outcomes. We anticipate that the data-analysis approach presented here can be generalized to other sets of biological assays and other chemical descriptors. Methods to assess which structural features of library members produce the greatest similarity in performance for a given set of biological assays should help prioritize synthesis decisions in second-generation library development targeting the underlying cell-biological processes. Methods to assess which structural features of library members produce the greatest variation in performance should help guide decisions about what synthetic methods need to be developed to make optimal small-molecule screening collections.
设计更好的小分子发现文库需要有方法来评估不同合成决策对所得文库成员生物学性能的影响。由于我们特别关注立体化学如何影响生物测定中的性能，我们制备了一个包含系统立体化学变化的二糖文库，对该文库进行不同生物效应的测定，并开发了方法来评估多个测定中成员之间性能的相似性。这些方法使我们能够探究哪些立体化学特征子集最能预测个体成员之间生物学性能模式的相似性，以及哪些特征会产生最大的结果差异。我们预计此处提出的数据分析方法可以推广到其他生物测定集和其他化学描述符。评估文库成员的哪些结构特征在给定的一组生物测定中产生最大性能相似性的方法，应有助于在针对潜在细胞生物学过程的第二代文库开发中确定合成决策的优先级。评估文库成员的哪些结构特征产生最大性能差异的方法，应有助于指导关于需要开发哪些合成方法以制备最佳小分子筛选文库的决策。
