Simulation exploration of novel natural antagonists targeting the N-methyl-D-aspartate receptor_Journal of Epilepsy

Authors：

GE Junliang ¹ ,  LIN Weihong ²

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;

Corresponding author：

LIN Weihong, Email: linwh@jlu.edu.cn

Keywords：

Epilepsy; Discovery Studio; N-methyl-D-aspartate receptor; Antagonist

DOI：

10.7507/2096-0247.202411010

Video：

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Abstract Full text Figures/Tables Video References Cited by

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.

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16.	Brodie MJ, Wroe SJ, Dean AD, et al. Efficacy and safety of remacemide versus carbamazepine in newly diagnosed epilepsy: comparison by sequential analysis. Epilepsy & Behavior, 2002, 3(2): 140-146.
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27.	Tokheim CJ, Papadopoulos N, Kinzler KW, et al. Evaluating the evaluation of cancer driver genes. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(50): 14330-14335.
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33.	Zhou HX, Wollmuth LP. Advancing NMDA receptor physiology by integrating multiple approaches. Trends in Neurosciences, 2017, 40(3): 129-137.
34.	Jetté N, Sander JW, Keezer MR. Surgical treatment for epilepsy: the potential gap between evidence and practice. The Lancet Neurology, 2016, 15(9): 982-994.
35.	Kossoff EH, Henry BJ, Cervenka MC. Efficacy of dietary therapy for juvenile myoclonic epilepsy. Epilepsy & Behavior, 2013, 26(2): 162-164.
36.	Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Archiv-European Journal of Physiology, 2010, 460(2): 525-542.
37.	Dingledine R, Borges K, Bowie D, et al. The glutamate receptor ion channels. Pharmacological Reviews, 1999, 51(1): 7-61.
38.	Goodkin HP, Sun C, Yeh JL, et al. GABA(A) receptor internalization during seizures. Epilepsia, 2007, 48(Suppl 5): 109-113.
39.	Hellier JL, White A, Williams PA, et al. NMDA receptor-mediated long-term alterations in epileptiform activity in experimental chronic epilepsy. Neuropharmacology, 2009, 56(2): 414-421.
40.	Peng WF, Ding J, Li X, et al. N-methyl-D-aspartate receptor NR2B subunit involved in depression-like behaviours in lithium chloride-pilocarpine chronic rat epilepsy model. Epilepsy Research, 2016, 119: 77-85.
41.	Wang JQ, Mao L. The ERK pathway: molecular mechanisms and treatment of depression. Molecular Neurobiology, 2019, 56(9): 6197-6205.
42.	Dwivedi R, Ramanujam B, Chandra PS, et al. Surgery for drug-resistant epilepsy in children. The New England Journal of Medicine, 2017, 377(17): 1639-1647.
43.	Tannich F, Barhoumi K, Rejeb A, et al. Ketamine, at low dose, decrease behavioural alterations in epileptic diseases induced by pilocarpine in mice. The International Journal of Neuroscience, 2020, 130(11): 1118-1124.

1. Moshé SL, Perucca E, Ryvlin P, et al. Epilepsy: new advances. Lancet (London, England), 2015, 385(9971): 884-98.
2. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia, 1989, 30(4): 389-399.
3. Perucca P, Scheffer IE, Kiley M. The management of epilepsy in children and adults. The Medical journal of Australia, 2018, 208(5): 226-233.
4. Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults. The Lancet Neurology, 2014, 13(11): 1114-1126.
5. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
6. Hauser WA, Beghi E. First seizure definitions and worldwide incidence and mortality. Epilepsia, 2008, 49(Suppl 1): 8-12.
7. Laroche SM, Helmers SL. The new antiepileptic drugs: scientific review. Jama, 2004, 291(5): 605-614.
8. Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nature Reviews Neuroscience, 2013, 14(6): 383-400.
9. Valdivielso JM, Eritja À, Caus M, et al. Glutamate-gated NMDA Receptors: insights into the function and signaling in the kidney. Biomolecules, 2020, 10(7): 1051.
10. Lau CG, Zukin RS. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nature Reviews Neuroscience, 2007, 8(6): 413-426.
11. Obara-Michlewska M, Ruszkiewicz J, Zielińska M, et al. Astroglial NMDA receptors inhibit expression of Kir4. 1 channels in glutamate-overexposed astrocytes in vitro and in the brain of rats with acute liver failure. Neurochemistry International, 2015, 88: 20-25.
12. Skowrońska K, Obara-Michlewska M, Czarnecka A, et al. Persistent overexposure to N-Methyl-D-Aspartate (NMDA) calcium-dependently downregulates glutamine synthetase, aquaporin 4, and Kir4. 1 channel in mouse cortical astrocytes. Neurotoxicity Research, 2019, 35(1): 271-280.
13. Huberfeld G, Menendez De La Prida L, Pallud J, et al. Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy. Nature Neuroscience, 2011, 14(5): 627-634.
14. Cendes F, Andermann F, Carpenter S, et al. Temporal lobe epilepsy caused by domoic acid intoxication: evidence for glutamate receptor-mediated excitotoxicity in humans. Annals of Neurology, 1995, 37(1): 123-126.
15. Dakshinamurti K, Sharma SK, Sundaram M. Domoic acid induced seizure activity in rats. Neuroscience Letters, 1991, 127(2): 193-197.
16. Brodie MJ, Wroe SJ, Dean AD, et al. Efficacy and safety of remacemide versus carbamazepine in newly diagnosed epilepsy: comparison by sequential analysis. Epilepsy & Behavior, 2002, 3(2): 140-146.
17. Chadwick DW, Betts TA, Boddie HG, et al. Remacemide hydrochloride as an add-on therapy in epilepsy: a randomized, placebo-controlled trial of three dose levels (300, 600 and 1200 mg/day) in a Q. I. D. regimen. Seizure, 2002, 11(2): 114-123.
18. Hanada T. Ionotropic glutamate receptors in epilepsy: a review focusing on AMPA and NMDA receptors. Biomolecules, 2020, 10(3): 464.
19. Pribish A, Wood N, Kalava A. A review of nonanesthetic uses of ketamine. Anesthesiology Research and Practice, 2020, 1: 5798285.
20. Kapur J. Role of NMDA receptors in the pathophysiology and treatment of status epilepticus. Epilepsia Open, 2018, 3(Suppl 2): 165-168.
21. Ghasemi M, Schachter SC. The NMDA receptor complex as a therapeutic target in epilepsy: a review. Epilepsy & Behavior, 2011, 22(4): 617-640.
22. Newman DJ. Developing natural product drugs: supply problems and how they have been overcome. Pharmacology & Therapeutics, 2016, 162: 1-9.
23. LI JW, Vederas JC. Drug discovery and natural products: end of an era or an endless frontier? Science (New York, NY), 2009, 325(5937): 161-165.
24. Zhong S, Li W, Bai Y, et al. Computational study on new natural compound agonists of stimulator of interferon genes (STING). PloS One, 2019, 14(5): e0216678.
25. Brooks BR, Brooks CL, Mackerell AD, et al. CHARMM: the biomolecular simulation program. Journal of Computational Chemistry, 2009, 30(10): 1545-1614.
26. Zhang Y, Ye F, Zhang T, et al. Structural basis of ketamine action on human NMDA receptors. Nature, 2021, 596(7871): 301-305.
27. Tokheim CJ, Papadopoulos N, Kinzler KW, et al. Evaluating the evaluation of cancer driver genes. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(50): 14330-14335.
28. Li J, Du H, Wu Z, et al. Interactions of omeprazole-based analogues with cytochrome P450 2C19: a computational study. Molecular BioSystems, 2016, 12(6): 1913-1921.
29. Wang E, Weng G, Sun H, et al. Assessing the performance of the MM/PBSA and MM/GBSA methods. 10. Impacts of enhanced sampling and variable dielectric model on protein-protein Interactions. Physical Chemistry Chemical Physics, 2019, 21(35): 18958-18969.
30. Haider MK, Bertrand HO, Hubbard RE. Predicting fragment binding poses using a combined MCSS MM-GBSA approach. Journal of Chemical Information and Modeling, 2011, 51(5): 1092-1105.
31. Kwon CS, Ripa V, Al-Awar O, et al. Epilepsy and neuromodulation-randomized controlled trials. Brain Sciences, 2018, 8(4): 69.
32. Neligan A, Hauser WA, Sander JW. The epidemiology of the epilepsies. Handbook of Clinical Neurology, 2012, 107: 113-133.
33. Zhou HX, Wollmuth LP. Advancing NMDA receptor physiology by integrating multiple approaches. Trends in Neurosciences, 2017, 40(3): 129-137.
34. Jetté N, Sander JW, Keezer MR. Surgical treatment for epilepsy: the potential gap between evidence and practice. The Lancet Neurology, 2016, 15(9): 982-994.
35. Kossoff EH, Henry BJ, Cervenka MC. Efficacy of dietary therapy for juvenile myoclonic epilepsy. Epilepsy & Behavior, 2013, 26(2): 162-164.
36. Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Archiv-European Journal of Physiology, 2010, 460(2): 525-542.
37. Dingledine R, Borges K, Bowie D, et al. The glutamate receptor ion channels. Pharmacological Reviews, 1999, 51(1): 7-61.
38. Goodkin HP, Sun C, Yeh JL, et al. GABA(A) receptor internalization during seizures. Epilepsia, 2007, 48(Suppl 5): 109-113.
39. Hellier JL, White A, Williams PA, et al. NMDA receptor-mediated long-term alterations in epileptiform activity in experimental chronic epilepsy. Neuropharmacology, 2009, 56(2): 414-421.
40. Peng WF, Ding J, Li X, et al. N-methyl-D-aspartate receptor NR2B subunit involved in depression-like behaviours in lithium chloride-pilocarpine chronic rat epilepsy model. Epilepsy Research, 2016, 119: 77-85.
41. Wang JQ, Mao L. The ERK pathway: molecular mechanisms and treatment of depression. Molecular Neurobiology, 2019, 56(9): 6197-6205.
42. Dwivedi R, Ramanujam B, Chandra PS, et al. Surgery for drug-resistant epilepsy in children. The New England Journal of Medicine, 2017, 377(17): 1639-1647.
43. Tannich F, Barhoumi K, Rejeb A, et al. Ketamine, at low dose, decrease behavioural alterations in epileptic diseases induced by pilocarpine in mice. The International Journal of Neuroscience, 2020, 130(11): 1118-1124.

Journal of Epilepsy

Latest ArticlesSimulation exploration of novel natural antagonists targeting the N-methyl-D-aspartate receptor

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