Ligand Residence Time at G-protein-Coupled Receptors-Why We Should Take Our Time To Study It

R.C. Hoffmann, M. Castro, A Rinken, R Leurs, S.J. Hill, H F Vischer

Research output: Contribution to JournalReview articleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)552-60
Number of pages9
JournalMolecular Pharmacology
Volume88
Issue number3
DOIs
Publication statusPublished - Sep 2015

Keywords

  • Amino Acid Sequence
  • Animals
  • Fluorescence Resonance Energy Transfer
  • Fluorescent Dyes
  • Humans
  • Kinetics
  • Ligands
  • Molecular Sequence Data
  • Protein Binding
  • Receptors, G-Protein-Coupled
  • Surface Plasmon Resonance
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Review

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