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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Binding Kinetics and Pathways of Ligands to GPCRs
Andrea Strasser1, Hans-Joachim Wittmann2, Roland Seifert3
1Department of Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Regensburg, Germany.
Trends in Pharmacological Sciences
|June 25, 2017
Summary
Drug-target residence time is crucial for drug development, impacting effectiveness. Molecular dynamics analysis reveals complex ligand-binding pathways for G-protein-coupled receptors (GPCRs).
Area of Science:
- Pharmacology and Biophysics
- Computational Chemistry
- Molecular Biology
Background:
- Traditional drug development prioritized target affinity and selectivity.
- Emerging evidence highlights drug-target residence time (off-rate) as a critical factor for drug efficacy.
- Ligand binding is increasingly understood as a multistep process involving intermediate binding sites.
Purpose of the Study:
- To review experimental ligand-binding data for G-protein-coupled receptors (GPCRs).
- To analyze GPCR binding pathways using molecular dynamics (MD).
- To elucidate the complex kinetics of drug binding to GPCRs.
Main Methods:
- Analysis of experimental ligand-binding data for GPCRs.
- Application of molecular dynamics (MD) simulations.
- Investigation of factors influencing ligand-receptor interactions.
Main Results:
- Drug-target residence time significantly affects drug on-rate and overall effectiveness.
- GPCR ligand binding involves complex, multistep pathways.
- Binding kinetics are influenced by receptor surface charge, binding channel/site interactions, and solvation.
Conclusions:
- Drug-target residence time is a key determinant of drug success.
- Understanding complex binding pathways is essential for rational drug design.
- Molecular dynamics provides valuable insights into GPCR-ligand interactions and kinetics.
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