Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 6, D-44227 Dortmund, Germany.
Biol Chem. 2018 Jun 27;399(7):691-710. doi: 10.1515/hsz-2018-0119.
DNA-encoded compound libraries are a highly attractive technology for the discovery of small molecule protein ligands. These compound collections consist of small molecules covalently connected to individual DNA sequences carrying readable information about the compound structure. DNA-tagging allows for efficient synthesis, handling and interrogation of vast numbers of chemically synthesized, drug-like compounds. They are screened on proteins by an efficient, generic assay based on Darwinian principles of selection. To date, selection of DNA-encoded libraries allowed for the identification of numerous bioactive compounds. Some of these compounds uncovered hitherto unknown allosteric binding sites on target proteins; several compounds proved their value as chemical biology probes unraveling complex biology; and the first examples of clinical candidates that trace their ancestry to a DNA-encoded library were reported. Thus, DNA-encoded libraries proved their value for the biomedical sciences as a generic technology for the identification of bioactive drug-like molecules numerous times. However, large scale experiments showed that even the selection of billions of compounds failed to deliver bioactive compounds for the majority of proteins in an unbiased panel of target proteins. This raises the question of compound library design.
DNA 编码化合物库是发现小分子蛋白配体的一种极具吸引力的技术。这些化合物库由小分子通过共价键与携带化合物结构可读信息的单个 DNA 序列连接而成。DNA 标记允许对大量化学合成的、类似药物的化合物进行高效合成、处理和检测。它们通过一种基于达尔文选择原理的高效通用检测方法在蛋白质上进行筛选。迄今为止，DNA 编码文库的选择已经鉴定了许多具有生物活性的化合物。其中一些化合物揭示了靶蛋白上以前未知的别构结合位点；一些化合物被证明作为化学生物学探针具有价值，用于揭示复杂的生物学；并且首次报道了可追溯到 DNA 编码文库的临床候选药物的例子。因此，DNA 编码文库作为一种通用技术，已经多次证明了其在生物医学科学中用于鉴定具有生物活性的类似药物的小分子的价值。然而，大规模实验表明，即使对数十亿种化合物进行选择，也未能为无偏靶蛋白组中的大多数蛋白质提供具有生物活性的化合物。这就提出了化合物库设计的问题。
