• 1. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China;
  • 2. Department of Neurology, The First Hospital of Jilin University, Changchun 130012, China;
LIN Weihong, Email: linwh@jlu.edu.cn
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Objective To screen and identify an ideal lead compound with potential inhibitory effects on N-methyl-D-aspartate receptor (NMDAR) from the ZINC15 drug database, promoting drug design and development to improve epilepsy treatment. Methods  Potential NMDAR inhibitors were identified through a series of computer-aided structural and chemical virtual screening techniques (Discovery Studio). Structure-based virtual screening was used to predict and further filter candidate compounds based on physicochemical, pharmacological, and toxicological properties. The binding affinity and chemical bond distribution between selected compounds and NMDAR were then analyzed, and the stability of the ligand-NMDAR complex in a natural environment was evaluated. Results  The study identified one novel natural compound from the ZINC15 database, with ZINC000096085903 showing low rodent carcinogenicity, no Ames mutagenicity, no developmental toxicity, and ideal physicochemical properties. This compound demonstrated high binding affinity and favorable interaction energy, with the ZINC000096085903-NMDAR complex exhibiting more favorable potential energy than the complex formed by NMDAR and the reference ligand ketamine. Furthermore, molecular dynamics simulation indicated that this complex remains stable in vivo and can inhibit NMDAR similarly to ketamine. Conclusion  ZINC000096085903 is an ideal lead compound for NMDAR inhibition. With higher binding affinity and stability when bound to NMDAR, as well as slower metabolism, ZINC000096085903 showed significant potential for long-term epilepsy treatment.

Citation: GE Junliang, LIN Weihong. Simulation exploration of novel natural antagonists targeting the N-methyl-D-aspartate receptor. Journal of Epilepsy, 2025, 11(1): 12-22. doi: 10.7507/2096-0247.202411010 Copy

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