NMDA receptor emerged as an attractive therapeutic target for the discovery and development of novel neuroprotective drugs [1-2]. NMDA receptor-mediated excitotoxicity was hypothesized to play a causative role in the etiology of ischemic stroke and several neurodegenerative diseases, such as schizophrenia, Parkinson's disease, and Alzheimer's disease. NMDA receptor antagonists are a class of anesthetics that work to competitively inhibit the action of the N-methyl-d-aspartate receptor.
The glutamate receptor of the N-methyl-d-aspartate (NMDA) subtype is a heterotetramer comprised of two GluN1 and two GluN2 subunits (that are also known as NR1 and NR2), two obligatory NR1 subunits and two regionally localized NR2 subunits. The structure can be divided by functional domains: heteromeric channel of a zeta subunit (GRIN1), an epsilon subunit (GRIN2A, GRIN2B, GRIN2C or GRIN2D) and a third subunit (GRIN3A or GRIN3B). All of them are disulfide-linked.
The primary function of NR1 subunits is the binding of co-agonist glycine and NR2 subunits responsible for the binding of the neurotransmitter glutamate. Activation of NMDA receptors requires the binding of glutamate or aspartate (the latter possesses a lower receptor stimulation activity). Besides, NMDARs require the binding of the co-agonist glycine for the efficient opening of the ion channel, which is a part of this receptor. The extracellular domain contains two globular structures: a modulatory domain and a ligand-binding domain . There are also several binding sites which are located in the channel's pore or the cavity formed by two subunits.
Life Chemicals has prepared a novel Library of more than 1,000 structurally diverse drug-like screening compounds of potential NMDA channel blockers, selected with molecular docking and divided into four subsets focused against each possible binding site (Fig. 1):
- competitive antagonists which bind to and block the glutamate binding site
- glycine antagonists which bind to and block the glycine binding site 
- noncompetitive antagonists which inhibit NMDARs by binding to allosteric sites (allosteric modulators) 
- noncompetitive antagonists which block the ion channel by binding to a site within its structure [6-7].
All compounds were additionally passed through PAINS and in-house MedChem filters to remove reactive/toxic/bad groups.
Figure 1. Schematic representation of reconstructed human GRIN1/GRIN2B dimer with marked glutamate/glycine (red spheres) and allosteric (yellow spheres) sites. The ion channel structure is colored with red and rendered to display its complex α-helical structure.
- Sharma, M.; Mittal, A.; Singh, A.; Jainarayanan, A. K.; Paliwal, S. K. Identification of Novel and Structurally Diverse N-Methyl-D-Aspartate Receptor Antagonists: Successful Application of Pharmacophore Modeling, Virtual Screening and Molecular Docking. bioRxiv2018, 314914. https://doi.org/10.1101/314914.
- Tai, K. K.; Blondelle, S. E. et al.. An N-Methyl-D-Aspartate Receptor Channel Blocker with Neuroprotective Activity. PNAS 2001, 98 (6), 3519–3524. doi: 10.1073/pnas.061449498.
- Kane LT, Costa BM. Identification of novel allosteric modulator binding sites in NMDA receptors: A molecular modeling study // J Mol Graph Model. 2015 Sep;61:204-13. doi: 10.1016/j.jmgm.2015.06.007.
- Jansen M., Dannhardt G.. Antagonists and agonists at the glycine site of the NMDA receptor for therapeutic interventions // European Journal of Medicinal Chemistry 38 (2003) 661-670.
- Laetitia Mony, James NC Kew, Martin J Gunthorpe. Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential // British Journal of Pharmacology (2009), 157, 1301–1317.
- Kashiwagi K, Masuko T, Nguyen CD, Kuno T, Tanaka I, Igarashi K, Williams K. Channel blockers acting at N-methyl-D-aspartate receptors: differential effects of mutations in the vestibule and ion channel pore //Mol Pharmacol. 2002 Mar; 61(3):533-45.
- Lee CH, Lü W, Michel JC, Goehring A. NMDA receptor structures reveal subunit arrangement and pore architecture // Nature. 2014 Jul 10;511(7508):191-7. doi: 10.1038/nature13548.