Many drug targets are embedded within the phospholipid bilayer of cellular membranes, including G protein-coupled receptors, ion channels, transporters and membrane-bound enzymes. Increasing evidence from biophysical and structural studies suggests that many small-molecule drugs commonly associate with these targets at binding sites at the protein–phospholipid interface. Without a direct path from bulk solvent to a binding site, a drug must first partition in the phospholipid membrane before interacting with the protein target. This membrane access mechanism necessarily affects the interpretation of potency data, structure–activity relationships, pharmacokinetics and physicochemical properties for drugs that target these sites. With an increasing number of small-molecule intramembrane binding sites revealed through X-ray crystallography and cryogenic electron microscopy, we suggest that ligand–lipid interactions likely play a larger role in small-molecule drug action than commonly appreciated. This Perspective introduces key concepts and drug design considerations to aid discovery teams operating within this target space, and discusses challenges and future opportunities in the field.

许多药物靶点嵌入细胞膜的磷脂双层中，包括 G 蛋白偶联受体、离子通道、转运蛋白和膜结合酶。来自生物物理和结构研究的越来越多的证据表明，许多小分子药物通常在蛋白质-磷脂界面的结合位点与这些靶点结合。如果没有从散装溶剂到结合位点的直接路径，药物必须首先在磷脂膜中分配，然后才能与蛋白质靶标相互作用。这种膜进入机制必然会影响针对这些位点的药物的效力数据、结构-活性关系、药代动力学和物理化学性质的解释。随着通过 X 射线晶体学和低温电子显微镜显示越来越多的小分子膜内结合位点，我们认为配体 - 脂质相互作用在小分子药物作用中的作用可能比通常认为的要大。该观点介绍了关键概念和药物设计考虑因素，以帮助发现团队在该目标空间内开展工作，并讨论该领域的挑战和未来机遇。