Ligand binding at the protein-lipid interface: strategic considerations for drug design

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.

Automated summary

Many drug targets are embedded within the phospholipid bilayer of cellular membranes, with drugs needing to partition in the membrane before interacting with the protein target. Ligand-lipid interactions may play a larger role in small-molecule drug action than commonly appreciated. Therefore, further research and interpretation are needed for potency data, structure-activity relationships, pharmacokinetics, and physicochemical properties of drugs targeting these sites.