Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA.
Chem Biol Drug Des. 2011 May;77(5):328-42. doi: 10.1111/j.1747-0285.2011.01100.x. Epub 2011 Mar 1.
Combinatorial libraries continue to play a key role in drug discovery. To increase structural diversity, several experimental methods have been developed. However, limited efforts have been performed so far to quantify the diversity of the broadly used diversity-oriented synthetic libraries. Herein, we report a comprehensive characterization of 15 bis-diazacyclic combinatorial libraries obtained through libraries from libraries, which is a diversity-oriented synthetic approach. Using MACCS keys, radial and different pharmacophoric fingerprints as well as six molecular properties, it was demonstrated the increased structural and property diversity of the libraries from libraries over the individual libraries. Comparison of the libraries to existing drugs, NCI diversity, and the Molecular Libraries Small Molecule Repository revealed the structural uniqueness of the combinatorial libraries (mean similarity <0.5 for any fingerprint representation). In particular, bis-cyclic thiourea libraries were the most structurally dissimilar to drugs retaining drug-like character in property space. This study represents the first comprehensive quantification of the diversity of libraries from libraries providing a solid quantitative approach to compare and contrast the diversity of diversity-oriented synthetic libraries with existing drugs or any other compound collection.
组合文库在药物发现中继续发挥着关键作用。为了增加结构多样性，已经开发了几种实验方法。然而，迄今为止，人们很少努力对广泛使用的基于多样性的合成文库的多样性进行量化。在此，我们报告了通过文库对文库获得的 15 种双二氮杂环组合文库的全面表征，这是一种基于多样性的合成方法。使用 MACCS 键、径向和不同的药效团指纹以及六个分子性质，证明了文库对文库的结构和性质多样性高于单个文库。将文库与现有药物、NCI 多样性和小分子库的分子库进行比较，揭示了组合文库的结构独特性（任何指纹表示的平均相似度<0.5）。特别是双环硫脲文库在保留药物性质的空间药物样特征方面与药物的结构差异最大。这项研究代表了对文库对文库多样性的首次全面量化，为比较和对比基于多样性的合成文库与现有药物或任何其他化合物库的多样性提供了一种可靠的定量方法。
