Compounds with multitarget activity (promiscuity) are increasingly sought in drug discovery. However, promiscuous compounds are often viewed controversially in light of potential assay artifacts that may give rise to false-positive activity annotations. We have reasoned that the strongest evidence for true multitarget activity of small molecules would be provided by experimentally determined structures of ligand–target complexes. Therefore, we have carried out a systematic search of currently available X-ray structures for compounds forming complexes with different targets. Rather unexpectedly, 1418 such crystallographic ligands were identified, including 702 that formed complexes with targets from different protein families (multifamily ligands). About half of these multifamily ligands originated from the medicinal chemistry literature, making it possible to consider additional target annotations and search for analogues. From 168 distinct series of analogues containing one or more multifamily ligands, 133 unique analogue-series-based scaffolds were isolated that can serve as templates for the design of new compounds with multitarget activity. As a part of our study, all of the multifamily ligands we have identified and the analogue-series-based scaffolds are made freely available.

中文翻译：

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基于X射线结构的具有不同家族目标活性的化合物的鉴定以及用于多目标配体设计的模板的生成

在药物发现中越来越多地寻求具有多靶标活性（混杂）的化合物。但是，经常根据可能引起假阳性活动注释的潜在检测伪像来对混杂化合物进行有争议的观察。我们认为，小分子真正的多靶标活性的最有力证据将由实验确定的配体-靶标复合物的结构提供。因此，我们对当前可用的X射线结构进行了系统搜索，以寻找形成具有不同目标的复合物的化合物。出乎意料的是，鉴定出了1418种这样的晶体学配体，其中包括702种与来自不同蛋白质家族的靶标（多家族配体）形成复合物。这些多族配体中约有一半来自药物化学文献，可以考虑其他目标注释并搜索类似物。从包含一个或多个多家族配体的168个不同的类似物系列中，分离出133个独特的基于类似物系列的支架，这些支架可以用作设计具有多靶标活性的新化合物的模板。作为我们研究的一部分，我们已经免费提供了所有已经确定的多家族配体以及基于类似物系列的支架。