title: Uncoupling the Structure-Activity Relationships of β2 Adrenergic Receptor Ligands from Membrane Binding.
abstract: 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.
authors.affiliation: Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Callum J
authors.initials: CJ
authors.lastname: Dickson
authors.affiliation: Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Viktor
authors.initials: V
authors.lastname: Hornak
authors.affiliation: Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Camilo
authors.initials: C
authors.lastname: Velez-Vega
authors.affiliation: Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Daniel J J
authors.initials: DJ
authors.lastname: McKay
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: John
authors.initials: J
authors.lastname: Reilly
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Sandham
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Duncan
authors.initials: D
authors.lastname: Shaw
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG , Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Fairhurst
authors.affiliation: Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre , Nottingham NG7 2UH, U.K.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Charlton
authors.affiliation: Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre , Nottingham NG7 2UH, U.K.
authors.forename: David A
authors.initials: DA
authors.lastname: Sykes
authors.affiliation: Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Pearlstein
authors.affiliation: Computer-Aided Drug Discovery, Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors.forename: Jose S
authors.initials: JS
authors.lastname: Duca
mesh_terms: D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D018343:Receptors, Adrenergic, beta-2