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Related Concept Videos

The Two-State Receptor Model01:29

The Two-State Receptor Model

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The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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Allosteric Regulation01:08

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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
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An antagonist is a drug that binds strongly to a receptor without activating it. An antagonist prevents other molecules, such as neurotransmitters or hormones, from binding to the receptor and triggering a cellular response. Such interaction effectively hinders the normal physiological processes mediated by the receptor, resulting in various pharmacological effects depending on the specific receptor targeted.
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Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
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Drug-receptor interaction describes the binding of receptors by drugs, but not all drug-receptor interactions result in activation and tissue response. For instance, the binding of agonists activates the receptor to generate a cellular reaction, while antagonists bind to receptors without causing their activation.
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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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Understanding CXCR2 antagonism with a dynamic allosteric ternary complex model.

Rui Li1, Richard Frisbie2, Fabien Vincent2

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The Journal of Pharmacology and Experimental Therapeutics
|March 1, 2025
PubMed
Summary

CXC chemokine receptor 2 (CXCR2) antagonists show variable antagonism. A dynamic allosteric model explains these differences, linking in vitro data to clinical outcomes for CXCR2 antagonists and other receptors.

Keywords:
Allosteric antagonismCXCR2Dynamic allosteric ternary complex modelPKPD modeling

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Area of Science:

  • Pharmacology
  • Biochemistry
  • Drug Discovery

Background:

  • CXC chemokine receptor 2 (CXCR2) antagonists exhibit varied antagonism patterns in vitro and in clinical studies.
  • Existing CXCR2 antagonists are allosteric but show inconsistent assay results and clinical efficacy.
  • Favorable drug exposures in clinical trials contrast with observed target modulation and efficacy issues.

Purpose of the Study:

  • To elucidate the mechanistic basis for inconsistent CXCR2 antagonist behavior using a dynamic allosteric ternary complex model.
  • To unify hypotheses explaining variable antagonism patterns observed in different experimental settings.
  • To bridge the gap between in vitro pharmacology and clinical outcomes for CXCR2 antagonists.

Main Methods:

  • Application of a dynamic allosteric ternary complex model to analyze in vitro binding and cell-based assay data.
  • Analysis of clinical neutrophil count data from CXCR2 antagonist studies using the proposed model.
  • Development of a unified hypothesis to explain surmountable vs. insurmountable antagonism based on receptor reserve and binding kinetics.

Main Results:

  • The dynamic allosteric ternary complex model successfully describes both in vitro and clinical data for CXCR2 antagonists.
  • Inconsistent antagonism patterns are attributed to receptor reserve and unsteady-state binding in cell-based assays.
  • Suboptimal potency, rather than fast binding kinetics, likely explains the lack of clinical pharmacology effect in some cases.

Conclusions:

  • The proposed model provides a unified explanation for the variable pharmacology of CXCR2 antagonists.
  • Receptor reserve and binding kinetics are critical factors influencing antagonist behavior in different assay conditions.
  • The model offers a framework for predicting clinical responses of allosteric antagonists for CXCR2 and other GPCRs.