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Identification of a novel P2X7 antagonist using structure-based virtual screening.

Gaia Pasqualetto1, Marika Zuanon1, Andrea Brancale2,3

  • 1School of Biosciences, Cardiff University, Cardiff, United Kingdom.

Frontiers in Pharmacology
|January 30, 2023
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Summary

Structure-based drug design identified GP-25, an indeno(1,2-b)pyridine derivative, as a P2X7 receptor antagonist. While ineffective against P2X4 receptors, GP-25 and its analogs offer a starting point for developing novel pain and inflammation therapeutics.

Keywords:
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Area of Science:

  • Biochemistry
  • Pharmacology
  • Medicinal Chemistry

Background:

  • P2X4 and P2X7 receptors are crucial ATP-gated ion channels implicated in neuropathic and inflammatory pain.
  • These receptors represent significant therapeutic targets for inflammatory diseases.
  • Structure-based design approaches for these targets remain underexplored compared to traditional screening methods.

Purpose of the Study:

  • To identify novel antagonists for human P2X4 and P2X7 receptors using structure-based drug design.
  • To explore the structure-activity relationships of identified compounds.
  • To investigate the binding modes of enantiomers for potential therapeutic development.

Main Methods:

  • Virtual screening of a large compound library against a molecular model of human P2X4.
  • Functional assays (calcium influx, dye uptake) to assess receptor antagonist activity.
  • Electrophysiology, cytotoxicity assays, and Schild analysis to characterize compound activity.
  • Molecular docking studies of compound enantiomers into P2X4 and P2X7 receptor models.

Main Results:

  • Virtual screening for P2X4 antagonists yielded no active compounds.
  • One compound, GP-25 (an indeno(1,2-b)pyridine derivative), showed significant antagonist activity at human P2X7 receptors (IC50 = 8.7 μM).
  • GP-25 and five analogs demonstrated P2X7 antagonist activity, allowing for structure-activity relationship analysis.
  • Docking studies suggested differential binding of GP-25 enantiomers, explaining the lack of P2X4 activity.

Conclusions:

  • GP-25 is a potent, orthosteric antagonist of human P2X7 receptors with potential for treating inflammatory conditions.
  • The identified indeno(1,2-b)pyridine scaffold is promising for developing selective P2X7 antagonists.
  • Understanding enantiomer-specific interactions provides a basis for optimizing drug design for P2X4/P2X7 targets.