Identifying potential GluN2B subunit containing N-Methyl-D-aspartate receptor inhibitors: an integrative in silico and molecular modeling approach

N-methyl-D-aspartate receptors (NMDARs), a class of ligand-gated ion channels, are involved in non-selective cation transport across the membrane. These are contained in glutamatergic synapse and produce excitatory effects leading to synaptic plasticity and memory function. GluN1-GluN2B, a subtype of NMDAR(s), has significant role in neurodegeneration, amyloid β (Aβ) induced synaptic dysfunction and loss. Thus, targeting and inhibiting GluN1-GluN2B may be effective in the management of neurodegenerative diseases including Alzheimer’s disease. In the present study, ligand and structure-based approaches were tried to identify the inhibitors. The pharmacophore, developed from co-crystallised ifenprodil, afforded virtual hits, which were further subjected through drug likeliness and PAINS filters to remove interfering compounds. Further comprehensive docking studies, free energy calculations and ADMET studies resulted in two virtual leads. The leads, ZINC257261614 and ZINC95977857 displayed good docking scores of −12.90 and −12.20 Kcal/mol and free binding energies of −60.83 and −61.83 Kcal/mol, respectively. The compounds were having acceptable predicted ADMET profiles and were subjected to molecular dynamic (MD) studies. The MD simulation produced stable complexes of these ligands with GluN1-GluN2B subunit having protein and ligand RMSD in acceptable limit. AbbreviationsAD Alzheimer's diseaseADME Absorption distribution metabolism and excretionATD Amino terminal domainBBB Blood-brain barrierCNS Central nervous systemCREB cAMP response element binding proteinCTD Carboxy-terminal domainGlu GlutamateGMQE Global model quality estimationHTVS High throughput virtual screeningHIA Human intestinal absorptionLGA Lamarckian genetic algorithmMD Molecular dynamicsMM-GBSA Molecular mechanics, the Generalised Born model for Solvent AccessibilityNMDAR N-methyl-D-aspartate receptorsPAINS Pan assay interference compoundsRMSD Root-mean square deviationRMSF Root-mean-square fluctuationSMARTS SMILES arbitrary target specificationSP standard precisionXP extra precision Communicated by Ramaswamy H. Sarma.