Drug & Target Development, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
J Med Chem. 2020 Oct 8;63(19):10742-10772. doi: 10.1021/acs.jmedchem.0c00523. Epub 2020 Jun 10.
Enzymes are common targets in high-throughput screening and related campaigns. An analysis of papers published between 1990 and 2018 showed that kinases were the most common enzymes investigated, fluorescence-based assays were the most common readout method, and cancer and bacterial infections were the most common therapeutic areas. High-throughput screening and fragment-screening campaigns published between 2017 and 2019 were analyzed in more depth, giving 75 examples of hit to lead development. Kinases, phosphatases, proteases, and peptidases were the most common targets, fluorescent assays were the most commonly used, and a wide variety of structural features were observed within the derived drugs. Hit frequency was largely independent of library size and positively correlated with ' value for the assay. Binding of metal ions to library compounds and substrates is an underappreciated source of false-positive results and unreproducible behavior.
酶是高通量筛选和相关研究中的常见靶点。对 1990 年至 2018 年间发表的论文进行分析后表明，激酶是研究最多的酶，基于荧光的检测方法是最常见的检测手段，癌症和细菌感染是最常见的治疗领域。对 2017 年至 2019 年发表的高通量筛选和片段筛选研究进行了更深入的分析，得到了 75 个从命中发现先导化合物的开发实例。激酶、磷酸酶、蛋白酶和肽酶是最常见的靶标，荧光检测法是最常用的方法，在所衍生的药物中观察到了各种各样的结构特征。命中频率在很大程度上与文库大小无关，而与检测的“ 值呈正相关。金属离子与文库化合物和底物的结合是假阳性结果和不可重现行为的一个被低估的来源。
