Computational identification of phytochemical NMDAR pore-targeting candidates for radiation-induced cognitive decline
Jemema Agnes Tripena Raj1,2, Abhishek Chatterjee1,2, Nikhil Gadewal3
1Department of Radiation Oncology, Advance Centre for Treatment Research and education in cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, 410210 India.
Abstract:
Radiation-induced cognitive decline (RICD) is a major late complication of cranial radiotherapy, particularly in pediatric brain tumor survivors. Memantine, an uncompetitive N-methyl-D-aspartate receptor (NMDAR) channel blocker, provides clinically relevant neuroprotection, However, the development of additional NMDAR-targeting candidates with favorable CNS penetration and pharmacological properties remains an unmet need. An integrated computational workflow was used to prioritize phytochemical NMDAR pore-targeting candidates. The memantine-bound NMDAR structure (PDB ID: 7SAD) guided pharmacophore modeling and virtual screening of 17,967 IMPPAT phytochemicals, followed by drug-likeness and CNS pharmacokinetic filtering. Prioritized compounds were evaluated by molecular docking, MM-GBSA/MM-PBSA, triplicate membrane-embedded molecular dynamics (MD), residue-contact and pore-geometry analyses, PCA/FEL, DFT, and in silico toxicity prediction. Filtering yielded 14,491 drug-like compounds, 1429 pharmacophore hits, 77 docking/MM-GBSA candidates, and seven compounds for detailed analysis. Triplicate 100 ns membrane simulations revealed ligand-dependent differences in binding energetics, interaction persistence, conformational sampling, and pore geometry. Dehydrocrenatidine (IMPHY010917), Skimmianine (IMPHY007265), Dehydrocrenatine (IMPHY007797), and Vasicinol (IMPHY004852) showed the most compelling complementary profiles, although no single compound consistently ranked highest across all descriptors. Dehydrocrenatidine, Skimmianine, Dehydrocrenatine, and Vasicinol are prioritized as putative NMDAR pore-targeting phytochemicals for RICD. Their complementary energetic, interaction, and conformational profiles provide a basis for experimental evaluation of NMDAR inhibition, CNS exposure, and radiation-relevant neuroprotection.
Supplementary Information:
The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00763-9.
