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Structure-based identification of GIRK2-PIP2 modulators: Integrative docking, MM-GBSA, ADMET, and molecular dynamics

Danko Jeremic1, Lydia Jiménez-Díaz1, Juan D Navarro-López1

  • 1Neurophysiology & Behavior Lab, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM) and Institute of Biomedicine (IB-UCLM), School of Medicine of Ciudad Real, University of Castilla-La Mancha, Ciudad Real, Spain.

Journal of Molecular Graphics & Modelling
|May 2, 2026
PubMed
Summary

Researchers screened over one million compounds to find new modulators for G protein-gated inwardly rectifying potassium (GIRK) channels, which are crucial for neuronal excitability. Promising candidates were identified that target the phosphatidylinositol-4,5-bisphosphate (PIP2) binding site.

Keywords:
ADMET profilingBinding affinity predictionKir3.2/GIRK2 potassium channelLeukotrienesMulti-target dockingPIP2-Binding siteStatinsVirtual screening

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Computational Chemistry

Background:

  • G protein-gated inwardly rectifying potassium (GIRK) channels regulate neuronal excitability and are therapeutic targets for CNS disorders.
  • Phosphatidylinositol-4,5-bisphosphate (PIP2) binding is essential for stabilizing the open state of GIRK channels.

Purpose of the Study:

  • To identify novel modulators of GIRK2 by targeting its PIP2-binding site.
  • To screen a large library of compounds for potential GIRK2 interaction.

Main Methods:

  • High-throughput virtual screening of over one million compounds against GIRK2 (PDB ID: 4KFM).
  • Docking simulations using Glide (SP, XP) with RMSD constraint to the native ligand.
  • Binding free energy estimation using Molecular Mechanics Generalized Born Surface Area (MM/GBSA).
  • Pharmacokinetic/physicochemical property analysis and 200 ns molecular dynamics (MD) simulations.

Main Results:

  • Identified known compounds (CID: 54365126, 7304563) as potential competitive GIRK2 modulators.
  • Revealed strong binding of metabolites like leukotrienes, resolvins, acyl-CoAs, and polyphosphates (ATP, thiamine-triphosphate) to GIRK2.
  • MD simulations showed stable interactions with key residues and binding modes similar to PIP2 for acyl-CoAs and polyphosphates.

Conclusions:

  • Identified promising small molecules and metabolites as potential GIRK2 modulators targeting the PIP2-binding site.
  • Highlighted potential cross-reactivity with other ion channels for some identified compounds.
  • Findings provide candidates for experimental validation and development of GIRK-PIP2 modulators.