Identification of novel allosteric modulator binding sites in NMDA receptors: A molecular modeling study.
The dysfunction of N-methyl-d-Aspartate receptors (NMDARs), a subtype of glutamate receptors, is correlated with schizophrenia, stroke, and many other neuropathological disorders. However, not all NMDAR subtypes equally contribute towards these disorders. Since NMDARs composed of different GluN2 subunits (GluN2A-D) confer varied physiological properties and have different distributions in the brain, pharmacological agents that target NMDARs with specific GluN2 subunits have significant potential for therapeutic applications. In our previous research, we have identified a family of novel allosteric modulators that differentially potentiate and/or inhibit NMDARs of differing GluN2 subunit composition. To further elucidate their molecular mechanisms, in the present study, we have identified four potential binding sites for novel allosteric modulators by performing molecular modeling, docking, and in silico mutations. The molecular determinants of the modulator binding sites (MBS), analysis of particular MBS electrostatics, and the specific loss or gain of binding after mutations have revealed modulators that have strong potential affinities for specific MBS on given subunits and the role of key amino acids in either promoting or obstructing modulator binding. These findings will help design higher affinity GluN2 subunit-selective pharmaceuticals, which are currently unavailable to treat psychiatric and neurological disorders.
Edward Via Virginia College of Osteopathic Medicine, Blacksburg, VA 24060, USA.
Lucas T
LT
Kane
Edward Via Virginia College of Osteopathic Medicine, Blacksburg, VA 24060, USA; Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg VA, 24061, USA. Electronic address: bcosta@vcom.vt.edu.
Blaise M
BM
Costa
D000495:Allosteric Site; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D003998:Dicarboxylic Acids / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface
D003998:Dicarboxylic Acids; C121673:Gprin1 protein, mouse; D008024:Ligands; C464436:NR2D NMDA receptor; D009419:Nerve Tissue Proteins; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate
Allosteric modulators; Docking; Modulator binding sites (MBSs); Molecular modeling; N-methyl-d-aspartate receptors (NMDARs)