Bioisostere Effects on the EPSA of Common Permeability-Limiting Groups,ACS Medicinal Chemistry Letters

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Bioisostere Effects on the EPSA of Common Permeability-Limiting Groups
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2022-05-23 , DOI: 10.1021/acsmedchemlett.2c00114
Andrew K Ecker ₁ , Dorothy A Levorse ₂ , Daniel A Victor ₂ , Matthew J Mitcheltree ₁

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Polar molecular surface area provides a valuable metric when optimizing properties as varied as membrane permeability and efflux susceptibility. The EPSA method to measure this quantity has had a substantial impact in medicinal chemistry, providing insight into the conformational and stereoelectronic features that govern the polarity of small molecules, targeted protein degraders, and macrocyclic peptides. Recognizing the value of bioisosteres in replacing permeation-limiting polar groups, we determined the effects of common amide, carboxylic acid, and phenol bioisosteres on EPSA, using matched molecular pairs within the Merck compound collection. Our findings reinforce EPSA’s utility in optimizing permeability, highlight bioisosteres within each class that are particularly effective in lowering EPSA and others, which despite widespread use, offer little to no such benefit. Our method for matched-pair identification is generalizable across large compound collections and, thus, may constitute a flexible platform to study the effects of bioisosterism both in EPSA and other in vitro assays.

中文翻译：

生物等排体对常见渗透性限制基团 EPSA 的影响

在优化诸如膜渗透性和流出敏感性等各种特性时，极性分子表面积提供了一个有价值的指标。测量该数量的 EPSA 方法对药物化学产生了重大影响，提供了对控制小分子、目标蛋白质降解剂和大环肽极性的构象和立体电子特征的深入了解。认识到生物电子等排物在替代渗透限制极性基团方面的价值，我们使用默克化合物系列中的匹配分子对确定了常见的酰胺、羧酸和苯酚生物电子等排物对 EPSA 的影响。我们的研究结果强化了 EPSA 在优化渗透性方面的效用，突出了每一类中对降低 EPSA 和其他物质特别有效的生物电子等排物，尽管这些物质被广泛使用，提供很少或没有这样的好处。我们的匹配对识别方法可推广到大型化合物集合中，因此可以构成一个灵活的平台来研究 EPSA 和其他体外测定中生物电子等排效应的影响。

更新日期：2022-05-23

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