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

G protein-gated inwardly rectifying potassium (GIRK) channels are key regulators of neuronal excitability, making them promising therapeutic targets for central nervous system disorders. Their activation depends on phosphatidylinositol-4,5-bisphosphate (PIP₂), which stabilizes the channel's open state. This study aimed to identify GIRK2 modulators targeting the PIP₂-binding site. Over one million compounds were screened against GIRK2 (PDB ID: 4KFM) using high-throughput virtual screening. To assure the accuracy and binding close to PIP₂-binding site, a core constraint was applied with a root-mean-square deviation (RMSD) below 2 Å with reference to the native ligand. The top-scoring ligands were redocked with Glide (SP, XP) and binding free energy was estimated using Molecular Mechanics Generalized Born Surface Area method. The most promising compounds were analyzed for pharmacokinetic/physicochemical properties, followed by molecular dynamics (MD) simulations over 200 ns in membrane bilayer. MD analysis revealed some known compounds (CID: 54365126 and 7304563) as potential competitive GIRK2 modulators, exhibiting stable interactions with residues critical for binding endogenous activators (PIP₂, cholesterol), and GIRK-acting drugs. Docking analyses also revealed strong binding to GIRK2 for various metabolites, including leukotrienes, resolvins, acyl-CoAs, and polyphosphates, including adenosine-triphosphate (ATP) and thiamine-triphosphate. Notably, some of the identified compounds are known to affect similar ion channels, indicating potential cross-reactivity with GIRK2. Furthermore, the binding modes of acyl-CoAs and polyphosphates closely resemble PIP₂'s hydrophobic and phosphate group engagement. Together, these findings offer promising candidates for experimental validation and further development of GIRK-PIP₂ modulators.