Hybrid virtual screening and molecular dynamics approach for identification of allosteric modulator of EAAT2

EAAT2, a glial protein that clears excess glutamate from synapses, regulates synaptic transmission, and prevents excitotoxicity in neurons is impaired by Aβ induced oxidative stress in neurodegenerative diseases like Alzheimer’s disease. Therefore, compounds that enhance EAAT2 function by reducing oxidative stress and excitotoxicity might be neuroprotective. The current study aimed to identify allosteric activators targeting EAAT2 in the treatment of AD using in-silico . Virtual screening identified promising candidates from the specs database and demonstrated excellent binding affinity with the allosteric pocket of EAAT2. ADMET studies determined the lipophilicity of the compounds and displayed good permeability across the BBB. MM-GBSA analysis further showed higher binding free energy for two compounds. Subsequently, molecular dynamics simulations confirmed the stability of the complex and its binding ability to the allosteric pocket of EAAT2. These findings identified the compound AK-968/15360623 as a promising lead molecule that could enhance EAAT2 function and prevent neurodegeneration in AD.