Konings D A, Wyatt J R, Ecker D J, Freier S M
ISIS Pharmaceuticals, Carlsbad, California 92008, USA.
J Med Chem. 1997 Dec 19;40(26):4386-95. doi: 10.1021/jm970503o.
Synthesis and testing of complex mixtures maximize the number of compounds that can be prepared and tested in a combinatorial library. When mixtures of compounds are screened, however, the identity of the compound(s) selected may depend on the deconvolution procedure employed. Previously, we developed a model system for evaluation of deconvolution procedures and used it to compare pooling strategies for iterative and noniterative deconvolution [Freier et al. J. Med. Chem. 1995, 38, 344-352]. We have now extended the model studies to include simulations of procedures with overlapping subsets such as subtractive pooling [Carell et al. Angew, Chem., Int. Ed. Engl. 1994, 33, 2061-2064], bogus coin pooling [Blake and Litzi-Davis. Bioconjugate Chem. 1992, 3, 510-513], and orthogonal pooling [D'Prez et al. J. Am. Chem. Soc. 1995, 117, 5405-5406]. These strategies required synthesis and testing of fewer subsets than did the more traditional nonoverlapping iterative strategies. The compounds identified using simulations of these strategies, however, were not the most active compounds in the library and were substantially less active than those identified by simulations of more traditional strategies.
复杂混合物的合成与测试可使组合库中能够制备和测试的化合物数量最大化。然而，当对化合物混合物进行筛选时，所选化合物的身份可能取决于所采用的反卷积程序。此前，我们开发了一个用于评估反卷积程序的模型系统，并利用它来比较迭代和非迭代反卷积的合并策略[弗雷尔等人，《药物化学杂志》，1995年，第38卷，第344 - 352页]。我们现在已将模型研究扩展到包括对具有重叠子集的程序进行模拟，如减法合并[卡雷尔等人，《德国应用化学》，国际英文版，1994年，第33卷，第2061 - 2064页]、假币合并[布莱克和利齐 - 戴维斯，《生物共轭化学》，1992年，第3卷，第510 - 513页]以及正交合并[德普雷兹等人，《美国化学会志》，1995年，第117卷，第5405 - 5406页]。与更传统的非重叠迭代策略相比，这些策略所需合成和测试的子集更少。然而，使用这些策略的模拟所鉴定出的化合物并非库中活性最高的化合物，其活性明显低于通过更传统策略的模拟所鉴定出的化合物。
