Uncoupling the Structure–Activity Relationships of β2 Adrenergic Receptor Ligands from Membrane Binding

Ligand binding to membrane proteins
may be significantly influenced
by the interaction of ligands with the membrane. In particular, the
microscopic ligand concentration within the membrane surface solvation
layer may exceed that in bulk solvent, resulting in overestimation
of the intrinsic protein–ligand binding contribution to the
apparent/measured affinity. Using published binding data for a set
of small molecules with the β2 adrenergic receptor, we demonstrate
that deconvolution of membrane and protein binding contributions allows
for improved structure–activity relationship analysis and structure-based
drug design. Molecular dynamics simulations of ligand bound membrane
protein complexes were used to validate binding poses, allowing analysis
of key interactions and binding site solvation to develop structure–activity
relationships of β2 ligand binding. The resulting relationships
are consistent with intrinsic binding affinity (corrected for membrane
interaction). The successful structure-based design of ligands targeting
membrane proteins may require an assessment of membrane affinity to
uncouple protein binding from membrane interactions.