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Molecular dynamics study-based mechanism of nefiracetam-induced NMDA receptor potentiation

Paper ID Volume ID Publish Year Pages File Format Full-Text
15042 1369 2015 9 PDF Available
Title
Molecular dynamics study-based mechanism of nefiracetam-induced NMDA receptor potentiation
Abstract

•Nefiracetam-induced N-methyl-d-aspartic acid (NMDA) receptor signaling was investigated.•Nefiracetam-induces NMDA receptor ligand binding domain conformation which favors glycine dissociation.•Nefiracetam replaces glycine within glycine-binding pocket upon dissociation.•The modulatory effect of nefiracetam on NMDA receptor intra-subunit communication and gating properties are discussed.

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 100 ns 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.

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Keywords
LBD, ligand-binding domain; GLUN1, subunit 1 of NMDA receptor; TMD, transmembrane domain; BSP-SLIM, binding site prediction-shape-based ligand matching with binding pocketNMDA receptor; Nefiracetam; Threonine-647; Gauche trap; Molecular dynamics
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Molecular dynamics study-based mechanism of nefiracetam-induced NMDA receptor potentiation
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Publisher
Database: Elsevier - ScienceDirect
Journal: Computational Biology and Chemistry - Volume 55, April 2015, Pages 14–22
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us