Identification of potential drug targets for treatment of refractory epilepsy using network pharmacology
Abstract
Epilepsy is the fourth most common neurological disease after migraine, stroke, and Alzheimer’s disease. Approximately one-third of all epilepsy cases are refractory to the existing anticonvulsants. Thus, there is an unmet need for newer antiepileptic drugs (AEDs) to manage refractory epilepsy (RE). Discovery of novel AEDs for the treatment of RE further retards for want of potential pharmacological targets, unavailable due to unclear etiology of this disease. In this regard, network pharmacology as an area of bioinformatics is gaining popularity. It combines the methods of network biology and polypharmacology, which makes it a promising approach for finding new molecular targets. This work is aimed at discovering new pharmacological targets for the treatment of RE using network pharmacology methods. In the framework of our study, the genes associated with the development of RE were selected based on analysis of available data. The methods of network pharmacology were used to select 83 potential pharmacological targets linked to the selected genes. Then, 10 most promising targets were chosen based on analysis of published data. All selected target proteins participate in biological processes, which are considered to play a key role in the development of RE. For 9 of 10 selected targets, the potential associations with different kinds of epilepsy have been recently mentioned in the literature published, which gives additional evidence that the approach applied is rather promising.
References
- 1. , Network pharmacology: The next paradigm in drug discovery, Nat Chem Biol 4 :682–690, 2008. Crossref, Medline, Google Scholar
- 2. , In silico method for identification of promising anticancer drug targets, SAR QSAR Environ Res 20 :755–766, 2009. Crossref, Medline, Google Scholar
- 3. , A DIseAse MOdule Detection (DIAMOnD) algorithm derived from a systematic analysis of connectivity patterns of disease proteins in the human interactome, PLoS Comput Biol 11 :e1004120, 2015. Crossref, Medline, Google Scholar
- 4. , GLADIATOR: A global approach for elucidating disease modules, Genome Med 9 :48, 2017. Crossref, Medline, Google Scholar
- 5. , Advanced Boolean modeling of biological networks applied to systems pharmacology, Bioinformatics 33 :1040–1048, 2017. Crossref, Medline, Google Scholar
- 6. , SystemsDock: A web server for network pharmacology-based prediction and analysis, Nucleic Acids Res 44: W507–W513, 2016. Crossref, Medline, Google Scholar
- 7. , How common are the “common” neurologic disorders? Neurology 68 :326–337, 2007. Crossref, Medline, Google Scholar
- 8. , ILAE official report: A practical clinical definition of epilepsy, Epilepsia 55 :475–482, 2014. Crossref, Medline, Google Scholar
- 9. , The natural history of epilepsy: An epidemiological view, J Neurol Neurosurg Psychiatr 75 :1376–1381, 2004. Crossref, Medline, Google Scholar
- 10. , Basic cellular and molecular mechanisms of refractory epilepsy: A review of current hypotheses, Mol Cell Epilepsy 1 :e17, 2014. Google Scholar
- 11. , Managing drug-resistant epilepsy: Challenges and solutions, Neuropsych Dis Treat 12 :2605–2616, 2016. Crossref, Medline, Google Scholar
- 12. , A novel mechanism underlying drug resistance in chronic epilepsy, Ann Neurol 53 :469–479, 2003. Crossref, Medline, Google Scholar
- 13. , Integrated network analysis reveals potentially novel molecular mechanisms and therapeutic targets of refractory epilepsies, PLoS One 12 :e0174964, 2017. Crossref, Medline, Google Scholar
- 14. , Network-based detection of disease modules and potential drug targets in intractable epilepsy, 8th Int Conf Systems Biology (ISB), pp. 132–140, 2014. Google Scholar
- 15. , Systems psychopharmacology: A network approach to developing novel therapies, World J Psychiatr 6 :66–83, 2016. Crossref, Medline, Google Scholar
- 16. , Expression of SHANK3 in the temporal neocortex of patients with intractable temporal epilepsy and epilepsy rat models, Cell Mol Neurobiol 37 :857–867, 2017. Crossref, Medline, Google Scholar
- 17. , Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline, Brain 139 :2420–2430, 2016. Crossref, Medline, Google Scholar
- 18. , SCN8A-related epilepsy with encephalopathy, GeneReviews 2016. Google Scholar
- 19. , Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy, Nat Med 21 :395–400, 2015. Crossref, Medline, Google Scholar
- 20. , Inhibition of mTOR pathway by rapamycin decreases P-glycoprotein expression and spontaneous seizures in pharmacoresistant epilepsy, J Mol Neurosci 61 :553–562, 2017. Crossref, Medline, Google Scholar
- 21. , A functional polymorphism of the microRNA-146a gene is associated with susceptibility to drug-resistant epilepsy and seizures frequency, Seizure 27 :60–65, 2015. Crossref, Medline, Google Scholar
- 22. , Associations between MDR1 C3435T polymorphism and drug-resistant epilepsy in the Polish population, Acta Neurol Belgica 117 :153–158, 2017. Crossref, Medline, Google Scholar
- 23. , W44X mutation in the WWOX gene causes intractable seizures and developmental delay: A case report, BMC Med Genet 17 :53, 2016. Crossref, Medline, Google Scholar
- 24. , Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy, Pharmacol Rep 69 :504–511, 2017. Crossref, Medline, Google Scholar
- 25. , Upregulation of breast cancer resistance protein and major vault protein in drug-resistant epilepsy, Seizure 47 :9–12, 2017. Crossref, Medline, Google Scholar
- 26. , The ATP-gated P2X7 receptor as a target for the treatment of drug-resistant epilepsy, Front Neurosci 11 :21, 2017. Crossref, Medline, Google Scholar
- 27. , Cortical gene expression correlates of temporal lobe epileptogenicity, Pathophysiology 23 :181–190, 2016. Crossref, Medline, Google Scholar
- 28. Noebels JL, Avoli M, Rogawski MA, Olsen RW and Delgado-Escueta AV (eds.), Jasper’s Basic Mechanisms of the Epilepsies, Bethesda MD, USA, 2012. Crossref, Google Scholar
- 29. , PASS: Prediction of activity spectra for biologically active substances, Bioinformatics 16 :747–748, 2000. Crossref, Medline, Google Scholar
- 30. , Prediction of the biological activity spectra of organic compounds using the PASS online web resource, Chem Heterocyclic Compd 50 :444–457, 2014. Crossref, Google Scholar
- 31. , New principle of search for compounds possessing anticonvulsive properties, Pharmaceut Chem J 32 :345–351, 1997. Crossref, Google Scholar
- 32. , Anticonvulsant mechanisms of piperine, a piperidine alkaloid, Channels (Austin) 9 :317–323, 2015. Crossref, Medline, Google Scholar
- 33. , Anti-convulsant potential of quinazolinones, RSC Adv 6 :44435–44455, 2016. Crossref, Google Scholar
- 34. , Pyridofuropyrrolo[1,2-a]pyrimidines and pyridofuropyrimido[1,2-a]azepines: New chemical entities (NCE) with anticonvulsive and psychotropic properties, RSC Adv 6 :49028–49038, 2016. Crossref, Google Scholar
- 35. , In silico prediction of anticonvulsant activity of N-(2,2,2-trichloro-1-hydroxyethyl) alkylcarboxamides, J Chem Pharmaceut Sci 10, 1099–1105, 2017. Google Scholar
- 36. , PASS targets: Ligand-based multi-target computational system based on a public data and naïve Bayes approach, SAR QSAR Environ Res 26 :783–793, 2015. Crossref, Medline, Google Scholar
- 37. , Pyrimidine-based inhibitors of dynamin I GTPase activity: Competitive inhibition at the Pleckstrin homology domain, J Med Chem 60 :349–361, 2017. Crossref, Medline, Google Scholar
- 38. , An overview of molecular fingerprint similarity search in virtual screening, Exp Opin Drug Discov 11 :137–148, 2016. Crossref, Medline, Google Scholar
- 39. , Docking and scoring in virtual screening for drug discovery: Methods and applications, Nat Rev Drug Discov 3 :935–949, 2004. Crossref, Medline, Google Scholar
- 40. , GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy, Ann Neurol 75 :147–154, 2014. Crossref, Medline, Google Scholar
- 41. , Kinin B1 and B2 receptors are overexpressed in the hippocampus of humans with temporal lobe epilepsy, Hippocampus 17 :26–33, 2007. Crossref, Medline, Google Scholar
- 42. , Drug resistance in epilepsy and the ABCB1 gene: The clinical perspective, Ind J Human Genet 17 :S12–S21, 2011. Crossref, Medline, Google Scholar
- 43. , Neuronal Nos (Nos1) polymorphism in patients with epilepsy: A pilot study, J Neurolog Sci 23 :20–25, 2006. Google Scholar
- 44. , The 2B-adrenergic receptor is mutant in cortical myoclonus and epilepsy, Ann Neurol 75 :77–87, 2014. Crossref, Medline, Google Scholar
- 45. , A novel subtype of astrocytes expressing TRPV4 (transient receptor potential vanilloid 4) regulates neuronal excitability via the release of gliotransmitters, J Biol Chem 289 :14470–14480, 2014. Crossref, Medline, Google Scholar
- 46. , Expression of -amyloid precursor protein in refractory epilepsy, Mol Med Rep 9 :1242–1248, 2014. Crossref, Medline, Google Scholar
- 47. , Down-regulation of Pin1 in temporal lobe epilepsy patients and mouse model, Neurochem Res 42 :1211–1218, 2017. Crossref, Medline, Google Scholar