RT Journal Article
SR Electronic
T1 Ligand Residence Time at G-protein–Coupled Receptors—Why We Should Take Our Time To Study It
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 552
OP 560
DO 10.1124/mol.115.099671
VO 88
IS 3
A1 Hoffmann, C.
A1 Castro, M.
A1 Rinken, A.
A1 Leurs, R.
A1 Hill, S. J.
A1 Vischer, H. F.
YR 2015
UL http://molpharm.aspetjournals.org/content/88/3/552.abstract
AB Over the past decade the kinetics of ligand binding to a receptor have received increasing interest. The concept of drug-target residence time is becoming an invaluable parameter for drug optimization. It holds great promise for drug development, and its optimization is thought to reduce off-target effects. The success of long-acting drugs like tiotropium support this hypothesis. Nonetheless, we know surprisingly little about the dynamics and the molecular detail of the drug binding process. Because protein dynamics and adaptation during the binding event will change the conformation of the protein, ligand binding will not be the static process that is often described. This can cause problems because simple mathematical models often fail to adequately describe the dynamics of the binding process. In this minireview we will discuss the current situation with an emphasis on G-protein–coupled receptors. These are important membrane protein drug targets that undergo conformational changes upon agonist binding to communicate signaling information across the plasma membrane of cells.