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Updated: Jan 15, 2026
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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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Biased Allosteric Modulation in GPCR Drug Discovery.
Jingzhi-Christina Zhou1,2, Michelle Z Li2,3, Alan Long2,4
1Department of Chemistry, Duke University, Durham, NC, USA.
Handbook of Experimental Pharmacology
|October 7, 2025
Summary
Allosteric modulators offer precise control over G protein-coupled receptors (GPCRs) signaling, enhancing drug discovery by reducing side effects. Biased allosteric modulators (BAMs) represent a promising strategy for developing targeted therapeutics.
Area of Science:
- Pharmacology
- Drug Discovery
- Molecular Biology
Background:
- Orthosteric drugs targeting G protein-coupled receptors (GPCRs) often lack subtype specificity and cause side effects.
- Allosteric modulators (AMs) bind to distinct sites, offering improved selectivity and pathway bias.
- Biased signaling and allosteric modulation represent a paradigm shift in GPCR drug discovery.
Purpose of the Study:
- To review the principles of biased signaling and allosteric modulation in GPCRs.
- To highlight strategies for designing biased allosteric modulators (BAMs).
- To explore the potential of BAMs for developing precision therapeutics.
Main Methods:
- Review of recent structural and biophysical studies on GPCR allosteric modulation.
- Analysis of biased signaling pathways involving G proteins and β-arrestins.
- Discussion of ligand design strategies for BAMs.
Main Results:
- Allosteric modulation allows fine-tuning of GPCR conformation and transducer engagement.
- AMs can preferentially direct signaling toward specific pathways (G protein or β-arrestin).
- Biased allosteric modulators (BAMs) selectively tune GPCR responses.
Conclusions:
- Allosteric modulation offers enhanced subtype selectivity and pathway bias compared to orthosteric approaches.
- BAMs hold significant promise for developing targeted GPCR therapies with improved efficacy and safety profiles.
- The convergence of biased signaling and allosteric modulation is revolutionizing GPCR drug discovery.
Keywords:
Allosteric modulationDrug discoveryFunctional selectivityG protein-coupled receptor (GPCR)Signaling biasTherapeutic developmentMore Related Videos
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