Open AccessExploring the kinetic selectivity of drugs targeting the β 1 ‐adrenoceptor
Author(s) -
Sykes David A.,
JiménezRosés Mireia,
Reilly John,
Fairhurst Robin A.,
Charlton Steven J.,
Veprintsev Dmitry B.
Publication year - 2022
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.978
Subject(s) - receptor–ligand kinetics , chemistry , kinetics , ligand (biochemistry) , partition coefficient , membrane , binding site , hydrophobic effect , static electricity , biophysics , protein data bank (rcsb pdb) , lipophilicity , selectivity , electrostatics , stereochemistry , receptor , biochemistry , organic chemistry , biology , electrical engineering , engineering , catalysis , physics , quantum mechanics
In this study, we report the β 1 ‐adrenoceptor binding kinetics of several clinically relevant β 1/2 ‐adrenoceptor (β 1/2 AR) agonists and antagonists. [ 3 H]‐DHA was used to label CHO‐β 1 AR for binding studies. The kinetics of ligand binding was assessed using a competition association binding method. Ligand physicochemical properties, including logD 7.4 and the immobilized artificial membrane partition coefficient ( K IAM ), were assessed using column‐based methods. Protein Data Bank (PDB) structures and hydrophobic and electrostatic surface maps were constructed in PyMOL. We demonstrate that the hydrophobic properties of a molecule directly affect its kinetic association rate ( k on ) and affinity for the β 1 AR. In contrast to our findings at the β 2 ‐adrenoceptor, K IAM , reflecting both hydrophobic and electrostatic interactions of the drug with the charged surface of biological membranes, was no better predictor than simple hydrophobicity measurements such as clogP or logD 7.4 , at predicting association rate. Bisoprolol proved kinetically selective for the β 1 AR subtype, dissociating 50 times slower and partly explaining its higher measured affinity for the β 1 AR. We speculate that the association of positively charged ligands at the β 1 AR is curtailed somewhat by its predominantly neutral/positive charged extracellular surface. Consequently, hydrophobic interactions in the ligand‐binding pocket dominate the kinetics of ligand binding. In comparison at the β 2 AR, a combination of hydrophobicity and negative charge attracts basic, positively charged ligands to the receptor's surface promoting the kinetics of ligand binding. Additionally, we reveal the potential role kinetics plays in the on‐target and off‐target pharmacology of clinically used β‐blockers.