Comprehensive and High-Throughput Exploration of Chemical Space Using Broadband19F NMR-Based Screening
Comprehensive and High-Throughput Exploration of Chemical Space Using Broadband19F NMR-Based Screening
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DOI：
10.1002/anie.202002463
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发表时间：
2020-06-22
影响因子：
16.6
通讯作者：
Frank, Andreas O.
中科院分区：
文献类型：
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作者：
Lingel, Andreas;Vulpetti, Anna;Frank, Andreas O.
基于片段的先导发现已经成为鉴定与疾病相关靶标有效相互作用的配体的基本方法。在众多的筛选技术中，氟检测NMR由于其高灵敏度、鲁棒性和易用性而受到欢迎。为了有效地探索化学空间，需要一个通用的NMR实验，一个合理设计的片段库，以及一个针对最大化合物数量和最短测量时间优化的样品组成。在这里，我们介绍了一种全面的方法，该方法能够在几天内有效组装包含近4000个片段的高质量和多样化的文库并筛选靶向特异性结合剂。该方法的核心是一种新的宽带弛豫编辑NMR实验，该实验在一次测量中涵盖了药物样（19）F基序的整个化学位移范围。我们的方法有助于识别不同的粘合剂和快速的新目标的配位能力评估。
Fragment-based lead discovery has become a fundamental approach to identify ligands that efficiently interact with disease-relevant targets. Among the numerous screening techniques, fluorine-detected NMR has gained popularity owing to its high sensitivity, robustness, and ease of use. To effectively explore chemical space, a universal NMR experiment, a rationally designed fragment library, and a sample composition optimized for a maximal number of compounds and minimal measurement time are required. Here, we introduce a comprehensive method that enabled the efficient assembly of a high-quality and diverse library containing nearly 4000 fragments and screening for target-specific binders within days. At the core of the approach is a novel broadband relaxation-edited NMR experiment that covers the entire chemical shift range of drug-like(19)F motifs in a single measurement. Our approach facilitates the identification of diverse binders and the fast ligandability assessment of new targets.