title: Molecular dynamics study-based mechanism of nefiracetam-induced NMDA receptor potentiation.
abstract: Plastic changes in the brain required for memory formation and long-term learning are dependent on N-methyl-d-aspartic acid (NMDA) receptor signaling. Nefiracetam reportedly boosts NMDA receptor functions as a basis for its nootropic properties. Previous studies suggest that nefiracetam potentiates the NMDA receptor activation, as a more potent co-agonist for glycine binding site than glycine, though the underlying mechanisms remain elusive. Here, using BSP-SLIM method, a novel binding site within the core of spiral β-strands-1-5 of LBD-GLUN1 has been predicted in glycine-bound GLUN1 conformation in addition to the glycine pocket in Apo-GLUN1. Within the core of spiral β-strands-1-5 of LBD-GLUN1 pocket, all-atom molecular dynamics simulation revealed that nefiracetam disrupts Arg523-glycine-Asp732 interaction resulting in open GLUN1 conformation and ultimate diffusion of glycine out of the clamshell cleft. Open GLUN1 conformation coerces other intra-chain domains and proximal inter-chain domains to sample inactivate conformations resulting in closure of the transmembrane gate via a novel gauche trap on threonine 647 (chi-1 dihedral (χ1)=-45° instead of +45°). Docking of nefiracetam into the glycine pocket reversed the gauche trap and meditates partial opening of the TMD gate within a time-scale of 100ns as observed in glycine-only state. All these results suggest that nefiracetam can favorably complete with glycine for GLUN1-LBD in a two-step process, first by binding to a novel site of GLUN1-LBD-NMDA receptor followed by disruption of glycine-binding dynamics then replacing glycine in the GLUN1-LBD cleft.
authors: Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, Japan; Center for Drug Discovery and Therapeutic Innovation, Nagasaki University, Japan.
authors: Olaposi I
authors: OI
authors: Omotuyi
authors: Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, Japan; Center for Drug Discovery and Therapeutic Innovation, Nagasaki University, Japan. Electronic address: ueda@nagasaki-u.ac.jp.
authors: Hiroshi
authors: H
authors: Ueda
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011619:Psychotropic Drugs / Q000737:chemistry; D011760:Pyrrolidinones / Q000737:chemistry*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
chemical_list: D011619:Psychotropic Drugs; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; C058876:nefiracetam
keywords: Gauche trap; Molecular dynamics; NMDA receptor; Nefiracetam; Threonine-647