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  • Perspective
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Ligand binding at the protein–lipid interface: strategic considerations for drug design

Nature Reviews Drug Discovery volume 20, pages 710–722 (2021)Cite this article

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Abstract

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.

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Fig. 1: Modes of receptor binding.
Fig. 2: Strategies for drug design at the protein–phospholipid interface.
Fig. 3: Structural data illuminate classical intramembrane binding sites.
Fig. 4: Structural data on emerging intramembrane binding sites.

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Acknowledgements

The authors thank F. Broccatelli, S. Staben, J. Tellis and E. Villemure for critical input on the manuscript.

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  1. Structural Biology, Genentech, Inc., South San Francisco, CA, USA

    Jian Payandeh

  2. Discovery Chemistry, Genentech, Inc., South San Francisco, CA, USA

    Matthew Volgraf

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The authors contributed equally to all aspects of the article.

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J.P. and M.V. are employees and shareholders of Genentech, Inc., a member of the Roche Group.

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Payandeh, J., Volgraf, M. Ligand binding at the protein–lipid interface: strategic considerations for drug design. Nat Rev Drug Discov 20, 710–722 (2021). https://doi.org/10.1038/s41573-021-00240-2

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