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 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.
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