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Exploring structure-promiscuity relationships using dual-site promiscuity cliffs and corresponding single-site analogs.
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2019-11-30 , DOI: 10.1016/j.bmc.2019.115238
Huabin Hu 1 , Jürgen Bajorath 1
Affiliation  

Currently available volumes of compounds and biological activity data enable large-scale analyses of compound promiscuity (multi-target activity). To aid in the exploration of structure-promiscuity relationships, promiscuity cliffs (PCs) were introduced previously. In analogy to activity cliffs, PCs were defined as pairs of structurally analogous compounds with large differences in the number of targets they are active against. Hence, PCs reveal small chemical modifications that are implicated in promiscuity. As introduced originally, PCs were identified by applying the matched molecular pair formalism and were thus confined to changes at a single substitution site. Herein, PCs with multiple substitution sites are introduced and a pilot study on a large collection of protein kinase inhibitors is reported, which provide excellent test cases for promiscuity analysis. For dual-site PCs (dsPCs), which dominated the distribution of multi-site PCs, an extended data structure was generated comprising a dsPC and two single-site analogs accounting for individual substitutions. Using a canonical representation, extended dsPCs are intuitive and easy to interpret from a chemical perspective. The analog quartet representing an extended dsPC is rich in structure-promiscuity relationship information and makes it possible to evaluate the potential interplay of chemical modifications implicated in promiscuity. Furthermore, extended dsPCs provide insights into possible experimental causes of apparent differences in analog promiscuity such as varying test frequencies. Hence, the newly introduced PC format should be of interest for exploring origins of compound promiscuity in medicinal chemistry and for formulating experimentally testable target hypotheses for analogs.

中文翻译:

使用双站点混杂悬崖和相应的单站点类似物探索结构—混杂关系。

当前可用的化合物量和生物活性数据可用于化合物混杂性(多目标活性)的大规模分析。为了帮助探索结构-混杂关系,先前已引入了混杂悬崖(PC)。与活动悬崖类似,PC被定义为成对的结构相似的化合物,它们具有针对性的靶标数量差异很大。因此,PC揭示了与滥交有关的小的化学修饰。如最初介绍的那样,通过应用匹配的分子对形式来识别PC,因此PC仅限于单个替换位点的变化。本文介绍了具有多个取代位点的PC,并报道了对大量蛋白激酶抑制剂的初步研究,这为混杂分析提供了出色的测试案例。对于主导多站点PC分布的双站点PC(dsPC),生成了扩展的数据结构,该结构包含dsPC和两个用于单个替换的单站点类似物。使用规范表示法,扩展的dsPC直观且易于从化学角度进行解释。代表扩展dsPC的模拟四重奏具有丰富的结构混杂关系信息,可以评估与混杂相关的化学修饰之间的潜在相互作用。此外,扩展的dsPC还提供了对模拟混杂的明显差异(例如变化的测试频率)的可能实验原因的见解。因此,
更新日期:2019-11-30
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