Identifying potential GluN2B subunit containing N-Methyl-D-aspartate receptor inhibitors: an integrative <i>in silico</i> and molecular modeling approach
Creators: name: Singh, Ravi
name: Ganeshpurkar, Ankit
name: Kumar, Devendra
name: Kumar, Dileep
name: Kumar, Ashok
name: Singh, Sushil Kumar
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biophysics
subject: Biochemistry
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Neuroscience
subject: Physiology
subject: Chemical Sciences not elsewhere classified
subject: Biological Sciences not elsewhere classified
subject: Infectious Diseases
subject: FOS: Health sciences

description: 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.
AbbreviationsADAlzheimer's diseaseADMEAbsorption distribution metabolism and excretionATDAmino terminal domainBBBBlood-brain barrierCNSCentral nervous systemCREBcAMP response element binding proteinCTDCarboxy-terminal domainGluGlutamateGMQEGlobal model quality estimationHTVSHigh throughput virtual screeningHIAHuman intestinal absorptionLGALamarckian genetic algorithmMDMolecular dynamicsMM-GBSAMolecular mechanics, the Generalised Born model for Solvent AccessibilityNMDARN-methyl-D-aspartate receptorsPAINSPan assay interference compoundsRMSDRoot-mean square deviationRMSFRoot-mean-square fluctuationSMARTSSMILES arbitrary target specificationSPstandard precisionXPextra precision Alzheimer's disease Absorption distribution metabolism and excretion Amino terminal domain Blood-brain barrier Central nervous system cAMP response element binding protein Carboxy-terminal domain Glutamate Global model quality estimation High throughput virtual screening Human intestinal absorption Lamarckian genetic algorithm Molecular dynamics Molecular mechanics, the Generalised Born model for Solvent Accessibility N-methyl-D-aspartate receptors Pan assay interference compounds Root-mean square deviation Root-mean-square fluctuation SMILES arbitrary target specification standard precision extra precision Communicated by Ramaswamy H. Sarma