Skip to main content

Research Repository

Advanced Search

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

Dickson, Callum J.; Hornak, Victor; Velez-Vega, Camilo; McKay, Daniel J.J.; Reilly, John; Sandham, David A.; Shaw, Duncan; Fairhurst, Robin A.; Charlton, Steven J.; Sykes, David A.; Pearlstein, Robert; Duca, Jose S.


Callum J. Dickson

Victor Hornak

Camilo Velez-Vega

Daniel J.J. McKay

John Reilly

David A. Sandham

Duncan Shaw

Robin A. Fairhurst

Profile Image

Professor of Molecular Pharmacology and Drug Discovery

David A. Sykes

Robert Pearlstein

Jose S. Duca


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 ?2 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 ?2 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.

Journal Article Type Article
Acceptance Date May 30, 2016
Online Publication Date Jun 7, 2016
Publication Date Jun 23, 2016
Deposit Date Jul 12, 2017
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 59
Issue 12
Pages 5780-5789
Public URL
Publisher URL