Exploring the kinetic selectivity of drugs targeting the β1-adrenoceptor

In this study, we report the β1-adrenoceptor binding kinetics of several clinically relevant β1/2-adrenoceptor (β1/2AR) 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 β2-adrenoceptor, a drug’s 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 β1-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 β1AR 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 β2AR, 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.

Three types of charged ligands based neutral phosphorescent iridium(III) complexes featuring nido-carborane: synthesis, structures, and solution processed organic light-emitting diode application

In view of the fact that coordination configuration and special functional groups are both important for the optical properties of phosphorescent iridium complexes materials, we have prepared a novel family...

Bases, solvates and salts: new benzimidazole- and pyridine-scaffolded ligands

The intermolecular interactions in the structures of a series of Schiff base ligands have been thoroughly studied. These ligands can be obtained in different forms, namely, as the free base 2-[(2E)-2-(1H-imidazol-4-ylmethylidene)-1-methylhydrazinyl]pyridine, C10H11N5, 1, the hydrates 2-[(2E)-2-(1H-imidazol-2-ylmethylidene)-1-methylhydrazinyl]-1H-benzimidazole monohydrate, C12H12N6·H2O, 2, and 2-{(2E)-1-methyl-2-[(1-methyl-1H-imidazol-2-yl)methylidene]hydrazinyl}-1H-benzimidazole 1.25-hydrate, C13H14N6·1.25H2O, 3, the monocationic hydrate 5-{(1E)-[2-(1H-1,3-benzodiazol-2-yl)-2-methylhydrazinylidene]methyl}-1H-imidazol-3-ium trifluoromethanesulfonate monohydrate, C12H13N6 +·CF3O3S−·H2O, 5, and the dicationic 2-{(2E)-1-methyl-2-[(1H-imidazol-3-ium-2-yl)methylidene]hydrazinyl}pyridinium bis(trifluoromethanesulfonate), C10H13N5 2+·2CF3O3S−, 6. The connection between the forms and the preferred intermolecular interactions is described and further studied by means of the calculation of the interaction energies between the neutral and charged components of the crystal structures. These studies show that, in general, the most important contribution to the stabilization energy of the crystal is provided by π–π interactions, especially between charged ligands, while the details of the crystal architecture are influenced by directional interactions, especially relatively strong hydrogen bonds. In one of the structures, a very interesting example of the nontypical F...O interaction was found and its length, 2.859 (2) Å, is one of the shortest ever reported.

The effect of charge on the uptake and resistance to reduction of platinum(iv) complexes in human serum and whole blood models

Platinum(iv) complexes can be modified by incorporating negatively charged ligands in order to inhibit cellular uptake and reduction in whole blood.

Charge effects at nano-bio interfaces: a model of charged gold nanoclusters on amylin fibrillation

Gold Nanocluster (AuNCs) with positive or negative charged ligands could inhibit or accelerate amylin fibrillation at Nano-bio interfaces, respectively.

THE CONDUCTIVITY OF THE MONOLAYER OF COMPLEXES OF DNA WITH QUANTUM DOTS IN THE PRESENCE OF INTERCALATING LIGANDS

The noncompetitive DNA hybridization and conductivity in the presence of non-charged ligands have been investigated and the comparison is made with the ligand-free case. It has been shown that the intercalating ligands enhance the sensitivity of the DNA chips as compared with the ligand-free case at the high enough concentration of ligands.