Computational Analysis of GRIN2A C1448R Variant in Epilepsy-Associated Intellectual Disability and their Structural Impact on NMDA Receptor Binding with Rapastinel and Dizocilpine

Authors

  • Sumaiya Yousaf Center of Biotechnology and Microbiology, University of Peshawar, 25120, Khyber Pakhtunkhwa, Pakistan Author
  • Rimsha Khan Center of Biotechnology and Microbiology, University of Peshawar, 25120, Khyber Pakhtunkhwa, Pakistan Author
  • Uzair Malik Center of Biotechnology and Microbiology, University of Peshawar, 25120, Khyber Pakhtunkhwa, Pakistan Author

Keywords:

Epilepsy GRIN2A, NMDA receptor, molecular docking, Rapastinel, Dizocilpine, C1448R mutation, ligand binding affinity, receptor conformation.

Abstract

Epilepsy-associated intellectual disability (ID) encompasses a spectrum of neurodevelopmental disorders often caused by genetic mutations affecting synaptic transmission. This study employed a dry-lab, in silico approach to identify and characterize high-confidence candidate genes implicated in epilepsy-related ID, with a focus on GRIN2A, a subunit of the N-Methyl-D-Aspartate (NMDA) receptor complex. The pathogenic variant, c.4342T>C (p.Cys1448Arg), was subjected to computational analysis, including pathogenicity prediction, protein stability evaluation, and molecular docking. Two ligands, Rapastinel (GLYX-13) and Dizocilpine (MK-801) were selected for docking based on their clinical and pharmacological relevance to NMDA receptor modulation.  Comparative docking revealed a reduction in binding affinity for Rapastinel (from −7.5 to −7.1 kcal/mol) and a slight increase for Dizocilpine (from −8.3 to −8.4 kcal/mol) in the mutant receptor. Protein–ligand interaction profiling showed that Rapastinel’s hydrogen bonding network was disrupted, while Dizocilpine retained hydrophobic interactions. Normal mode analysis indicated increased structural flexibility, with lower eigenvalues and elevated B-factors in the mutant complex, suggesting destabilized receptor conformation. These findings provide molecular insight into how the C1448R mutation may contribute to synaptic dysfunction in epilepsy-associated intellectual disability. This study underscores the utility of computational biology in exploring genotype–phenotype relationships and may guide future drug development efforts targeting GRIN2A related epileptic disorders.

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Published

2025-06-24

How to Cite

Computational Analysis of GRIN2A C1448R Variant in Epilepsy-Associated Intellectual Disability and their Structural Impact on NMDA Receptor Binding with Rapastinel and Dizocilpine. (2025). INTERNATIONAL JOURNAL OF APPLIED AND CLINICAL RESEARCH, 3(2), 20-30. https://www.ijacr.com/index.php/home/article/view/23