INSILICO AND PHARMACOLOGICAL APPROACHES TO NOVEL THERAPEUTICS FOR NEUROPATHIC PAIN: A REVIEW OF FOCUS ON GLUTAMATERGIC AND CALCIUM CHANNEL PATHWAYS
Main Article Content
Keywords
Neuropathic pain, insilico drug design, glutamatergic pathways, calcium channels, NMDA receptors, voltage-gated calcium channels
Abstract
Background: Neuropathic pain is a complicated clinical problem with maladaptive alterations in nociceptive pathways, affecting millions of people worldwide. Conventional painkiller medications do not be sufficient to treat pain; new treatment strategies involve particular molecular processes.
Objective: The review discusses the present status of integrated computational and experimental models involving the discovery and testing of new therapeutic agents in the management of neuropathic pain through the activation of glutamatergic and calcium channel pathways.
Methods: The literature search was performed as a full search in PubMed, Scopus, and Web of Science databases of 2015-2024 publications. Keywords were neuropathic pain, in silico drug design, glutamatergic pathways, calcium channels and pharmacological validation.
Results: Recent developments in computational drug design have established many potential drugs that would inhibit NMDA receptors, AMPA receptors, and voltage-gated calcium channels (VGCCs). The combined insilico-experimental techniques have been shown to be successful at 15-25% in q.v.f.i.c.d.t., a lot more successful than the conventional high-throughput screening technologies.
Conclusions: Computational modelling plus rigorous pharmacological validation is a potentially useful approach to developing drugs to treat neuropathic pain, but there is still work to do to translate promising preclinical findings into clinical success.
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14. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765-1769.
15. Liu XJ, Gingrich JR, Vargas-Caballero M, Dong YN, Mazarati A, Sankar R, et al. Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nat Med. 2008;14(12):1325-1332.
16. Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg. 2003;97(4):1108-1116.
17. Tao YX. AMPA receptor trafficking in inflammation-induced dorsal horn central sensitization. Neurosci Bull. 2012;28(4):111-120.
18. Neugebauer V. Metabotropic glutamate receptors—important modulators of nociception and pain behavior. Pain. 2002;98(1-2):1-8.
19. Fundytus ME. Glutamate receptors and nociception: implications for the drug treatment of pain. CNS Drugs. 2001;15(1):29-58.
20. Dolphin AC. Calcium channel auxiliary α2δ and β subunits: trafficking and one step beyond. Nat Rev Neurosci. 2012;13(8):542-555.
21. Zamponi GW, Striessnig J, Koschak A, Dolphin AC. The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev. 2015;67(4):821-870.
22. Li CY, Song YH, Higuera ES, Luo ZD. Spinal dorsal horn calcium channel alpha-2-delta-1 subunit upregulation contributes to peripheral nerve injury-induced tactile allodynia. J Neurosci. 2004;24(39):8494-8499.
23. Bourinet E, Altier C, Hildebrand ME, Trang T, Salter MW, Zamponi GW. Calcium-permeable ion channels in pain signaling. Physiol Rev. 2014;94(1):81-140.
24. Todorovic SM, Jevtovic-Todorovic V. T-type voltage-gated calcium channels as targets for the development of novel pain therapies. Br J Pharmacol. 2011;163(3):484-495.
25. Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res. 2007;73(2):137-150.
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27. Barabási AL, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human disease. Nat Rev Genet. 2011;12(1):56-68.
28. Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4(11):682-690.
29. Zhang GB, Li QY, Chen QL, Su SB. Network pharmacology: a new approach for chinese herbal medicine research. Evid Based Complement Alternat Med. 2013;2013:621423.
30. Veluchamy A, Hébert HL, Meng W, Palmer CNA, Smith BH. Systematic review of genetic association studies in people with chronic pain. Pain. 2018;159(8):1452-1468.
31. LaCroix-Fralish ML, Ledoux JB, Mogil JS. The Pain Genes Database: An interactive web browser of pain-related transgenic knockout studies. Pain. 2007;131(1-2):3.e1-4.
32. Zoubarev A, Hamer KM, Keshav KD, McCarthy EL, Santos JRC, Van Rossum T, et al. Gemma: a resource for the reuse, sharing and meta-analysis of expression profiling data. Bioinformatics. 2012;28(17):2272-2273.
33. Karakas E, Furukawa H. Crystal structure of a heterotetrameric NMDA receptor ion channel. Science. 2014;344(6187):992-997.
34. Wu J, Yan Z, Li Z, Qian X, Lu S, Dong M, et al. Structure of the voltage-gated calcium channel Cav1.1 at 3.6 Å resolution. Nature. 2016;537(7619):191-196.
35. Sali A, Blundell TL. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993;234(3):779-815.
36. Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46(W1):W296-303.
37. Erlanson DA, Fesik SW, Hubbard RE, Jahnke W, Jhoti H. Twenty years on: the impact of fragments on drug discovery. Nat Rev Drug Discov. 2016;15(9):605-619.
38. Yang SY. Pharmacophore modeling and applications in drug discovery: challenges and recent advances. Drug Discov Today. 2010;15(11-12):444-450.
39. Cramer RD, Patterson DE, Bunce JD. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc. 1988;110(18):5959-5967.
40. Chen H, Engkvist O, Wang Y, Olivecrona M, Blaschke T. The rise of deep learning in drug discovery. Drug Discov Today. 2018;23(6):1241-1250.
41. Lo YC, Rensi SE, Torng W, Altman RB. Machine learning in chemoinformatics and drug discovery. Drug Discov Today. 2018;23(8):1538-1546.
42. Yang K, Swanson K, Jin W, Coley C, Eiden P, Gao H, et al. Analyzing learned molecular representations for property prediction. J Chem Inf Model. 2019;59(8):3370-3388.
43. Scroggs RS, Fox AP. Calcium current variation between acutely isolated adult rat dorsal root ganglion neurons of different size. J Physiol. 1992;445:639-658.
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Sep 29, 2025
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Disha Patel, Dr. Nishkruti R. Mehta, Mr. Khinya Ram, & Dr. Pragnesh Patani. (2025). INSILICO AND PHARMACOLOGICAL APPROACHES TO NOVEL THERAPEUTICS FOR NEUROPATHIC PAIN: A REVIEW OF FOCUS ON GLUTAMATERGIC AND CALCIUM CHANNEL PATHWAYS. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1153-1165. https://doi.org/10.53555/ywptsr98
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Author Biographies
Disha Patel
Student, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Nishkruti R. Mehta
Professor & Head, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Mr. Khinya Ram
Assitant Professor, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Pragnesh Patani
Principal, Khyati College of Pharmacy, Palodiya, Ahmedabad
How to Cite
Disha Patel, Dr. Nishkruti R. Mehta, Mr. Khinya Ram, & Dr. Pragnesh Patani. (2025). INSILICO AND PHARMACOLOGICAL APPROACHES TO NOVEL THERAPEUTICS FOR NEUROPATHIC PAIN: A REVIEW OF FOCUS ON GLUTAMATERGIC AND CALCIUM CHANNEL PATHWAYS. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1153-1165. https://doi.org/10.53555/ywptsr98