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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
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Covalent allosteric modulation: An emerging strategy for GPCRs drug discovery
Yuemin Bian1, Jaden Jungho Jun1, Jacob Cuyler1
1Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, Pittsburgh, PA, 15261, United States; NIH National Center of Excellence for Computational Drug Abuse Research, Pittsburgh, PA, 15261, United States.
European Journal of Medicinal Chemistry
|August 21, 2020
Summary
This review explores covalent allosteric modulators for G-protein-coupled receptors (GPCRs), highlighting their potential for enhanced drug discovery through increased potency and selectivity.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Structural Biology
Background:
- G-protein-coupled receptors (GPCRs) are key drug targets.
- Allosteric modulation offers subtype selectivity and reduced resistance.
- Covalent modulators enhance binding potency and duration.
Purpose of the Study:
- To review the design of covalent allosteric modulators for GPCRs.
- To discuss the structural basis and advantages of allosteric modulation.
- To explore the benefits and common warheads of covalent ligands.
Main Methods:
- Review of structural biology of allosteric pockets.
- Analysis of different allosteric modulator types.
- Case studies of covalent allosteric modulator design for GPCR classes.
Main Results:
- Covalent allosteric modulation combines benefits of both approaches.
- Successful design strategies for Class A, B, and C GPCRs are presented.
- Case studies demonstrate increased potency and prolonged action.
Conclusions:
- Covalent allosteric modulators represent a promising strategy in drug discovery.
- This approach offers improved therapeutic potential for GPCR-targeted drugs.
- Future perspectives and limitations of this drug design modality are discussed.
Keywords:
Allosteric modulatorCannabinoid receptorsCovalent bondG-protein-coupled receptorGPCRGlucagon-like peptide-1 receptorMetabotropic glutamate receptorsMore Related Videos
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