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−l...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
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American Chemical Society
2016
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| Online Access: | https://eprints.nottingham.ac.uk/38577/ |
| _version_ | 1848795644069675008 |
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| author | 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. |
| author_facet | 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. |
| author_sort | Dickson, Callum J. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:35:21Z |
| format | Article |
| id | nottingham-38577 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:35:21Z |
| publishDate | 2016 |
| publisher | American Chemical Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-385772020-05-04T17:49:27Z https://eprints.nottingham.ac.uk/38577/ 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. 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. American Chemical Society 2016-05-30 Article PeerReviewed 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 and Duca, Jose S. (2016) Uncoupling the structure–activity relationships of β2 adrenergic receptor ligands from membrane binding. Journal of Medicinal Chemistry, 59 (12). pp. 5780-5789. ISSN 1520-4804 http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00358 doi:10.1021/acs.jmedchem.6b00358 doi:10.1021/acs.jmedchem.6b00358 |
| spellingShingle | 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. Uncoupling the structure–activity relationships of β2 adrenergic receptor ligands from membrane binding |
| title | Uncoupling the structure–activity relationships of β2 adrenergic receptor ligands from membrane binding |
| title_full | Uncoupling the structure–activity relationships of β2 adrenergic receptor ligands from membrane binding |
| title_fullStr | Uncoupling the structure–activity relationships of β2 adrenergic receptor ligands from membrane binding |
| title_full_unstemmed | Uncoupling the structure–activity relationships of β2 adrenergic receptor ligands from membrane binding |
| title_short | Uncoupling the structure–activity relationships of β2 adrenergic receptor ligands from membrane binding |
| title_sort | uncoupling the structure–activity relationships of β2 adrenergic receptor ligands from membrane binding |
| url | https://eprints.nottingham.ac.uk/38577/ https://eprints.nottingham.ac.uk/38577/ https://eprints.nottingham.ac.uk/38577/ |