Screening of small-molecule libraries is a productive method for identifying both chemical probes of disease-related targets and potential starting points for drug discovery. In this article, we focus on strategies such as diversity-oriented synthesis that aim to explore novel areas of chemical space efficiently by populating small-molecule libraries with compounds containing structural features that are typically under-represented in commercially available screening collections. Drawing from more than a decade's worth of examples, we highlight how the design and synthesis of such libraries have been enabled by modern synthetic chemistry, and we illustrate the impact of the resultant chemical probes and drug leads in a wide range of diseases.

小分子文库的筛选是一种有效的方法，可用于识别疾病相关靶标的化学探针和药物发现的潜在起点。在本文中，我们重点关注诸如面向多样性的合成之类的策略，这些策略旨在通过使用包含结构特征的化合物填充小分子库来有效地探索化学空间的新领域，而这些结构特征通常在商业上可用的筛选集合中代表性不足。我们借鉴了十多年的例子，重点介绍了现代合成化学如何设计和合成此类文库，并说明了由此产生的化学探针和药物先导化合物对多种疾病的影响。