Ligand binding to membrane proteins may be significantly influenced by the interaction of ligands with the membrane. The apparent activity of ligands may therefore be composed of 1) ligand partitioning into the membrane and 2) intrinsic binding of ligand to the membrane protein.<br/><br/>Using published data of a set of small molecules with measured β2 adrenergic receptor binding, we demonstrate how correcting for membrane binding provides a path to derive meaningful structure-activity relationships, which could then be used for traditional structure based drug design.<br/><br/>Molecular dynamics simulations of ligand-membrane protein complexes allow validation of binding poses and analysis of key interactions to develop a structure-activity relationship of β2 ligand binding. The successful structure based design of ligands targeting membrane proteins may require an assessment of membrane partitioning to uncouple protein binding from membrane interactions.

Uncoupling the structure-activity relationship of β2 adrenergic receptor ligands from membrane binding

250th National Meeting (2015)

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