Waldman M, Li H, Hassan M
Molecular Simulations Inc., 9685 Scranton Road, San Diego, CA 92121, USA.
J Mol Graph Model. 2000 Aug-Oct;18(4-5):412-26, 533-6. doi: 10.1016/s1093-3263(00)00071-1.
Various approaches to measuring and optimizing molecular diversity of combinatorial libraries are presented. The need for different diversity metrics for libraries consisting of discrete molecules ("cherry picking") vs libraries formed from combinatorial R-group enumeration (array-based selection) is discussed. Ideal requirements for diversity metrics applied to array-based selection are proposed, focusing, in particular, on the concept of incremental diversity, i.e., the change in diversity as redundant or nonredundant molecules are added to a compound collection or combinatorial library. Several distance and cell-based diversity functions are presented and analyzed in terms of their ability to satisfy these requirements. These diversity functions are applied to designing diverse libraries for two test cases, and the performance of the diversity functions is assessed. Issues associated with redundant molecules in the virtual library are discussed and analyzed using one of the test examples. The results are compared to reagent-based diversity optimizations, and it is shown that a product-based diversity protocol can result in significant improvements over a reagent-based scheme based on the diversity obtained for the resulting libraries.
本文介绍了测量和优化组合文库分子多样性的各种方法。讨论了对于由离散分子组成的文库（“挑选精华”）与由组合R基团枚举形成的文库（基于阵列的选择）而言，采用不同多样性度量的必要性。提出了应用于基于阵列选择的多样性度量的理想要求，尤其着重于增量多样性的概念，即当将冗余或非冗余分子添加到化合物集合或组合文库时多样性的变化。介绍了几种基于距离和基于单元的多样性函数，并根据它们满足这些要求的能力进行了分析。将这些多样性函数应用于两个测试案例的多样化文库设计，并评估了多样性函数的性能。使用其中一个测试示例讨论并分析了与虚拟文库中冗余分子相关的问题。将结果与基于试剂的多样性优化进行比较，结果表明，基于所得文库的多样性，基于产物的多样性方案相较于基于试剂的方案可带来显著改进。
