Charlton, S. J. | bioRxiv Science

bioRxiv2021

Exploring the kinetic selectivity of drugs targeting the β1-adrenoceptor

In this study, we report the {beta}1-adrenoceptor binding kinetics of several clinically relevant {beta}1/2-adrenoceptor ({beta}1/2AR) agonists and antagonists. We demonstrate that the physicochemical properties of a molecule directly affect its kinetic association rate (kon) and affinity for the target. In contrast to our findings at the {beta}2-adrenoceptor, a drugs immobilized artificial membrane partition coefficient (KIAM), 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 log P or logD7.4, characterized by a distribution between water and a non-aqueous organic phase (e.g. n-octanol) at predicting association rate. Overall, this suggests that hydrophobic interactions rather than a combination of polar and hydrophobic interactions play a more prominent role in dictating the binding of these ligands to the {beta}1-adrenoceptor. Using a combination of kinetic data, detailed structural and physicochemical information we rationalize the above findings and speculate that the association of positively charged ligands at the {beta}1AR 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 {beta}2AR, a combination of hydrophobicity and negative charge attracts basic, positively charged ligands to the receptors 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 {beta}-blockers.

pharmacology and toxicology↗

bioRxiv2021

Fentanyl binds to the mu-opioid receptor via the lipid membrane and transmembrane helices

Overdose deaths from synthetic opioids, such as fentanyl, have reached epidemic proportions in the USA and are increasing worldwide. Fentanyl is a potent opioid agonist, that is less well reversed by naloxone than morphine. Due to fentanyls high lipophilicity and elongated structure we hypothesised that its unusual pharmacology may be explained by a novel binding mode to the -opioid receptor (MOPr). By employing coarse-grained molecular dynamics simulations and free energy calculations, we determined the routes by which fentanyl and morphine access the orthosteric pocket of MOPr. Morphine accesses MOPr via the aqueous pathway; first binding to an extracellular vestibule, then diffusing into the orthosteric pocket. In contrast, fentanyl takes a novel route; first partitioning into the membrane, before accessing the orthosteric site by diffusing through a ligand-induced gap between the transmembrane helices. This novel lipophilic route may explain the high potency and lower susceptibility of fentanyl to reversal by naloxone.

pharmacology and toxicology↗