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Jeremic, D.

Publications and source records attributed to Jeremic, D..

2 recordsLinked to original sources
bioRxiv2025

Structure-based identification of GIRK2-PIP2 modulators among known drugs and metabolites using 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 channels open state. A deeper understanding of GIRK-PIP2 interactions could uncover new physiological roles and pave the way for therapies that modulate channel function. This study aimed to advance the targeting of GIRK channels at the PIP2-binding site. Over one million compounds were screened against GIRK2 (PDB ID: 4KFM) using high-throughput virtual screening. A core constraint with a root-mean-square deviation (RMSD) < 2 [A] was applied to assure the accuracy and binding close to PIP2-binding site. 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 three known compounds (Rosuvastatin, 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 can affect similar ion channels, indicating potential cross-reactivity with GIRK2. Furthermore, the binding modes of acyl-CoAs and polyphosphates closely resemble PIP2s hydrophobic and phosphate group engagement. Together, these findings offer promising candidates for experimental validation and therapeutic development. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/653795v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1325e66org.highwire.dtl.DTLVardef@1d3835corg.highwire.dtl.DTLVardef@1550df3org.highwire.dtl.DTLVardef@107007e_HPS_FORMAT_FIGEXP M_FIG C_FIG Abbreviations: ADMET - Absorption, Distribution, Metabolism, Elimination, Toxicity; CID - PubChem Compound Identification; MM-GBSA - Molecular Mechanics with Generalized Born and Surface Area solvation; RMSD - Root-Mean-Square Deviation; SP - Standard Precision; PIP2 - phosphatidylinositol-4,5-bisphosphate; XP - Extra Precision. HIGHLIGHTSO_LIMulti-target screening identifies selective modulators of the GIRK2 channel C_LIO_LILigands target the PIP2-binding site, a novel interface for GIRK2 modulation C_LIO_LIMM-GBSA confirms binding affinity and ligand stability post-docking C_LIO_LIDynamics and bioinformatics predict selectivity and off-target interactions C_LIO_LIStatins and leukotriene-modifying drugs are strong GIRK2 modulator candidates C_LI

bioinformatics↗
bioRxiv2023

Systematic characterization of a non-transgenic Amyloid-beta1-42 amyloidosis model: synaptic plasticity and memory deficits in female and male mice

BackgroundOne of the neuropathological hallmarks of Alzheimers disease (AD) is amyloid-{beta} (A{beta}) accumulation in the hippocampus that causes its dysfunction. This disruption includes excitatory/inhibitory imbalance, synaptic plasticity and oscillatory activity impairments, and memory deficits. Although AD prevalence is higher in women than men, the possible sex difference is scarcely explored and information from amyloidosis transgenic mice models is contradictory. Thus, given the lack of data of the early amyloidosis stages in females, the aim of this study was to systematically characterize the effect of an intracerebroventricular (icv.) injection of A{beta}1-42 on hippocampal-dependent memory, and on associated activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse, in both male and female mice. MethodsTo do so, we evaluated long term potentiation (LTP) with ex vivo electrophysiological recordings and spatial (working, short- and long-term) and exploratory habituation memory using Barnes maze or open field habituation tasks respectively. ResultsWe found that A{beta}1-42 administration impairs all forms of memory evaluated, regardless the sex, in a long-lasting manner (up to 17 days post-injection). Furthermore, LTP was inhibited at a postsynaptic level, both in males and females, and a long-term depression (LTD) was induced for the same prolonged period, which could underly memory deficits. ConclusionsIn conclusion, our results provide further evidence of the shifting of LTP/LTD threshold due to a single icv. A{beta}1-42 injection, which underly cognitive deficits in early stages of AD. These long-lasting cognitive and functional alterations in males and females validate this model for the study of early amyloidosis in both sexes, thus offering a solid alternative to the inconsistence of amyloidosis transgenic mice models.

neuroscience↗