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Time-dependent ligand-receptor binding kinetics and functionality in a heterodimeric receptor model.

Antonio J Ortiz1, Víctor Martín2, David Romero3

  • 1Laboratory of Molecular Neuropharmacology and Bioinformatics, Unitat de Bioestadística and Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain; Unitat de Neurociència Traslacional, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona, Spain.

Biochemical Pharmacology
|May 19, 2024
PubMed
Summary

Quantitative models of G protein-coupled receptors (GPCRs) heteromerization are crucial for drug development. This study presents a model for two-drug interactions at heterodimeric GPCRs, aiding combination therapy design.

Keywords:
Binding kineticsDrug combination therapyDynamical systemsMathematical modelingReceptor heterodimerization

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Area of Science:

  • Pharmacology
  • Biophysics
  • Computational Biology

Background:

  • G protein-coupled receptors (GPCRs) form heteromers in the central nervous system (CNS) and other tissues.
  • Receptor heteromerization fine-tunes signaling pathways, offering therapeutic potential.
  • Quantitative models are essential for pharmacologists to investigate these mechanisms.

Purpose of the Study:

  • To develop a time-dependent model for the binding kinetics and functionality of preformed heterodimeric GPCRs with two drugs.
  • To explore scenarios where one drug is in excess and its concentration is reduced to mitigate side effects while maintaining efficacy through allosteric modulation.
  • To provide a framework for understanding and quantifying drug combinations for therapeutic purposes.

Main Methods:

  • Development of a time-dependent mathematical model.
  • Analysis of binding kinetics and receptor functionality for heterodimeric GPCRs.
  • Consideration of two drug scenarios: excess of both drugs or excess of only one drug.

Main Results:

  • The model quantifies the effects of two drugs on heterodimeric GPCRs, considering different concentrations and efficacies.
  • Demonstrated how allosteric effects can maintain therapeutic efficacy when reducing the concentration of a drug causing side effects.
  • Included allosteric modulation by endogenous compounds and synthetic bivalent ligands.

Conclusions:

  • Receptor heteromerization provides a mechanistic basis for understanding drug interactions in combination therapy.
  • The developed model offers a quantitative framework for optimizing drug combinations, particularly for opioid-induced analgesia and side effect management.
  • This approach facilitates the rational design of drug combination therapies by elucidating complex pharmacological effects.