Receptor Residence Time
- Laura Heitman
It is now emerging that, next to ‘traditional’ receptor affinity, the total duration of the ligand-receptor interaction, the so-called residence time, can have a crucial impact on the ligand’s effectiveness and selectivity. This has been demonstrated in isolated cases, and coined very differently (e.g., insurmountable antagonism, slow dissociation (kinetics), pseudo-irreversible interaction, binary complex residence time, etc.). Typical examples in the GPCR field are the M3-receptor selectivity of the antagonist tiotropium and the long-acting ‘sartans’ (angiotensin receptor antagonists); they show a prolonged interaction with their target compared to reference ligands.
It will not surprise you that we are currently studying what the impact of residence time is, not only on adenosine and other receptors, but also on “anti-targets” such as the Kv11.1 (hERG) channel. We thought this concept was so important that we set up a consortium entirely devoted to the kinetic aspects of drug action, called K4DD – kinetics for drug discovery, which is now sponsored with over 20 M€ by the European Union. We have a separate link to this program on our homepage.
Yu Z, van Veldhoven JP, Louvel J, 't Hart IM, Rook MB, van der Heyden MA, Heitman LH, IJzerman AP. Structure-Affinity Relationships (SARs) and Structure-Kinetics Relationships (SKRs) of Kv11.1 Blockers.J Med Chem. 2015
Guo D, Hillger JM, IJzerman AP, Heitman LH. Drug-target residence time-a case for G protein-coupled receptors. Med Res Rev. 2014, 34(4):856-92.
Louvel J, Guo D, Agliardi M, Mocking TA, Kars R, Pham TP, Xia L, de Vries H, Brussee J, Heitman LH, IJzerman AP. Agonists for the adenosine A1 receptor withtunable residence time. A Case for nonribose 4-amino-6-aryl-5-cyano-2-thiopyrimidines. J Med Chem. 2014, 57(8):3213-22.
Guo D, Xia L, van Veldhoven JP, Hazeu M, Mocking T, Brussee J, IJzerman AP, Heitman LH. Binding kinetics of ZM241385 derivatives at the human adenosine A2A receptor.ChemMedChem. 2014, 9(4):752-61.
Guo D, van Dorp EJ, Mulder-Krieger T, van Veldhoven JP, Brussee J, IJzerman AP, Heitman LH. Dual-Point Competition Association Assay: A Fast and High-Throughput Kinetic Screening Method for Assessing Ligand-Receptor BindingKinetics. J Biomol Screen. 2013, 18(3):309-20.
Guo D, Mulder-Krieger T, IJzerman AP, Heitman LH. Functional efficacy of adenosine A2A receptor agonists is positively correlated to their receptor residence time. Br J Pharmacol. 2012, 166(6):1846-59.