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Abstract
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.
| Abbreviations | ||
| AD | = | Alzheimer's disease |
| ADME | = | Absorption distribution metabolism and excretion |
| ATD | = | Amino terminal domain |
| BBB | = | Blood-brain barrier |
| CNS | = | Central nervous system |
| CREB | = | cAMP response element binding protein |
| CTD | = | Carboxy-terminal domain |
| Glu | = | Glutamate |
| GMQE | = | Global model quality estimation |
| HTVS | = | High throughput virtual screening |
| HIA | = | Human intestinal absorption |
| LGA | = | Lamarckian genetic algorithm |
| MD | = | Molecular dynamics |
| MM-GBSA | = | Molecular mechanics, the Generalised Born model for Solvent Accessibility |
| NMDAR | = | N-methyl-D-aspartate receptors |
| PAINS | = | Pan assay interference compounds |
| RMSD | = | Root-mean square deviation |
| RMSF | = | Root-mean-square fluctuation |
| SMARTS | = | SMILES arbitrary target specification |
| SP | = | standard precision |
| XP | = | extra precision |
Communicated by Ramaswamy H. Sarma
Acknowledgements
The authors would also like to extend their gratitude toward Professor David A. Case, Department of Chemistry & Chemical Biology, Rutgers University, New Jersey, USA for providing support granting a license for Amber 18. Molecular graphics and analyses performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311 is also thankfully acknowledged.
Disclosure statement
No potential conflict of interest was reported by the authors.