Researcher 2018;10(5)

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1 Interaction Study Of Antioxidants With Progressive Myoclonus Epilepsy By Molecular Docking Techniques Ruchi Yadav AMITY Institute of Biotechnology, AMITY University, Uttar Pradesh Lucknow, UP, INDIA Abstract: Progressive Myoclonus Epilepsy (PME) is a rare epilepsy syndrome caused by number of genetic disorders. This syndrome contains myoclonic seizures and chronic seizures along with progressive neurological decline. Oxidative stress can result into mild or severe form of these diseases and remain the cause of several other diseases such as cardiovascular diseases, neurological diseases, malignancies, renal disease, diabetes, inflammatory, skin diseases, aging, respiratory diseases, liver diseases, and different type of viral infection. The evaluation of the effectiveness of various, antioxidants is being targeted due to clinical, trials of several neurodegenerative diseases. In this study we have seen the effectiveness of antioxidants against Progressive Myoclonus Epilepsy disease. Docking is done using Schrödinger software, interaction studies shows that Resveratrol is potential drug against myoclonus epilepsy. Further study shows that antioxidants can be better inhibitor of myoclonus epilepsy disease. [Ruchi Yadav. Interaction Study Of Antioxidants With Progressive Myoclonus Epilepsy By Molecular Docking Techniques. Researcher 2018;10(5):32-38]. ISSN (print); ISSN (online) doi: /marsrsj Keywords: Lafora disease; antioxidants; Resveratrol; Schrödinger software; docking. 1. Introduction Progressive myoclonus epilepsy (PME) include muscle contractions (myoclonus) and seizures (epilepsy) [1]. PME is collection of diseases involving the Central nervous system and shows similar symptoms of progression muscle contraction that worsen overtime and epilepsy [2]. Myoclonus is more severe than epilepsy since there are drugs that can treat either muscle contraction or seizures but not both [3]. Researches show that there is absence of motor neurons coordination including myoclonus even when patient shows no symptoms of seizures [4]. Other symptoms include mental related problems like depression, loss of memory, and with course of time it worsens [5]. Other complications include Urinary tract infection, Gastric and bladder related problems [6]. There is three identified forms of PME depending upon symptoms: Lafora disease: It is an autosomal recessive disorder that is it is the disease which occurs only whenever two copies of defected gene inherited by child, one from each parent [7]. Lafora disease is characterised by epileptic myoclonus seizures and dementia [8] (continuous loss of memory and other intellectual function) [9]. A second group of PME disease belonging to the class of cerebral storage diseases usually involves myoclonus, visual problem dementia and dystonia [10]. Another group of PME disorders is the class of system degenerates often is accompanied by action myoclonus seizures and problem with balance and walking [11]. Many of the PME diseases begins in childhood or adolescence [12]. Reticular reflex myoclonus is considered to be a type of generalised epilepsy that originates in the brain stem [13]. Table 1 list the proteins that belongs to different class of PME and function of proteins. Progressive myoclonic epilepsies (PME) is a syndrome that is collection of disease which include neurological disorders due to defects in neurons development involving central nervous system disorders, ataxia [14], progressive myoclonus (muscle contractions), cognitive defects, these symptoms increases with due course of time [15]. There are different classes of PME on the basis of symptoms and proteins involved major types include EPM1 (Unverricht-Lundborg disease), EMP2 (myoclonic epilepsy of Lafora) [16]. Research has been done to identify potential inhibitor and drug target involved in PME. Genes involved in these diseases include mutation in CSTB gene, EPM2A gene or NHLRC1 gene [17]. 32

2 Sn.O Uniprot Id Laforin 2 P Q6VVB1 4 P48553 Table 1. List of proteins involved in progressive myoclonus epilepsy Protein Name Diseases Function DNA polymerase subunit gamma 1 E3 ubiquitin protein ligase Trafficking protein particle complex subunit 10 Epilepsy progressive myoclonic 2 (EPM 2) progressive external opthalnoplagea with mitochondrial DNA deletion, autosomal dominant Epilepsy progressive myoclonic 2 (epm 2) 5 P04080 Cystatin b Epilepsy progressive myoclonic 1 6 Q13510 Acid ceradimise 7 Q96mt3 Prickle like protein 1 8 Q Q96mp8 10 P48547 Golgi SNAP receptor complex member 2 BTB/POZ domain containing protein KCTDT Potassium voltage gated channel sub family c memeber 11 P27544 Ceramide synthase 1 Nil Farber lipogranulomatosis (FRBR L) Epilepsy progressive myoclonic 1b (EPM 1B) Epilepsy progressive myoclonic 6(epm 6) Epilepsy progressive myoclonic 3 with or without intracellular inclusions (EPM3) epilepsy progressive myoclonic 7(EPM7) Epilepsy progressive myoclonic 8(EPM 8) 12 Q9WUA5 Laforin Disrupts on phenotype 13 Q03252 Lamin b 2 partial acquired lipodystrophy 14 Q9NQV8 15 Q716J9 PR domain zinc finger protein b splicing endonuclease subunit 16 Q713G6 Prickle like protein 2 Epilepsy progressive myoclonic 10(EPM 10) Pontocerebellar-hypoplasia 4(PCM 4) Spinocerebellar ataxia with epilepsy (SCAE) Involved in the clearance of toxic polyglucosan and proteins aggregates via multiple pathways Involved in the replication of mitochondrial DNA Involved in clearance of toxic polyglucosan play a role in vesicular transport from endoplasmic reticulum to Golgi Intracellular thiol proteinase inhibitor Hydrolysis of the sphingolipid ceramide Involved in the planar cell polarity pathway Involved in transport of proteins from the cis mediated Golgi to the trans Golgi network Involved in the control of excitability of cortical neurons Mediates the voltage dependent potassium ion Involved in the production of sphingolipids containing mainly one fatty acid donor Impaired behavioural responses ataxia Lamins are component of nuclear lamina Involved in the control of steroidogenesis A complex is responsible for identification and cleavage of the splices site in pre trna Zinc ion binding 2. Material And Methods 2.1 Protein Targets In this study five protein targets have been studied. Proteins are retrieved from PDB database [18] with PDB Ids: 3FI2, 5HTB, 4RKK, 3FV8, 3FI3. 1) 3FI2: Crystal structure of JNK 3 with aminopyrazole Inhibitor SR ) 5HTB: Crystal structure of haspin (GSG2) in complex with substrate inhibitor ARC ) 4RKK: Structure of a product bound phosphatase (Laforin). 4) 3FV8: JNK3 bound to piperazine amide inhibitor, Also exhibit map kinase activity, monomeric structure. 5) 3FI3: Crystal structure of JNK 3 with imidazole inhibitor SR-3737, Indazole linked inhibitors attested by SR-3737 are inhibitors of both JNK 3 and p Ligands Antioxidants are selected from Pubchem database [19]. Ten ligands files were downloaded 33

3 table 2 shows the list of ligands that are used for docking protein targets and to identify best inhibitor. Table 2. List of ligands for Docking Sn.O Pubchem Id Ligand Name Molecular Formula LIDOCAINE C 14 H 22 N 2 O EPIPROPIDINE C 16 H 28 N 2 O RES 2664 C 25 H 22 BrNO RESVERATROL C 14 H 12 O MAXIMOL A C 28 H 22 O POLYDATIN C 20 H 22 O PINOSTILBINE C 15 H 14 O RES C 23 H 30 O GNETIN C C 28 H 22 O PTEROSTILBENE C 32 H 30 O Docking Docking of protein with ligands as listed in table 2 is done by Glide docking [20] program using Schrödinger software suite [21]. Glide score were analyzed and ligand protein interaction map is studied to identify type of interaction between target protein and ligand. 3. Results and Discussion Docking result is studied and G-scores (Glide score) is analyzed to identify best ligand. Ligand having minimum energy is studied for ligand protein interaction map. Table 3 shows the G-Scores of five target protein and ten ligands. G-scores highlighted in yellow shows the best interaction with protein. Protein JNK3 (PDB ID: 3FI3, 3FV8, 3F12) shows the best interaction with Pinostilbine ligand and Resveratrol.JNK3 protein are class of JNKs (c-jun N- terminal Kinase signaling pathway) belongs to MAP kinase that is mitogen activated protein kinase family [22]. JNK3 are related with neuronal damage in hippocampal neurons.jnk3 are largely located in hippocampus region and disruption JNK3 gene shows reduced seizure action and degradation in neuronal apoptosis [23]. Researchers suggest that JNK3 can be important to study mechanism of neurological disorders and hence found to be significant for use in drug targets for epilepsy and upcoming therapeutics. Protein/ Ligands Lidocaine Epipropidine Res 2664 Table 3. Docking scores of ligand with protein Resveratrol Maximol A Polydatin Pinostilbine Res Gnetin C Pterostilbene 3FI NA HTB NA NA 4RKK NA 3FV NA 3FI NA Haspin protein (PDB ID: 5HTB) have best interaction with Resveratrol. Haspin (haploid germ cell specific nuclear protein kinase) belongs to class of serine/threonine kinase and involved I phosphorylation during meiosis [24]. and Laforin protein (PDB ID: 4RKK) interacts with Polydatin. Laforin protein belongs to Lafora disease that is characterized by Lafora bodies caused by growth of polyglucosan inclusion majorly in cytoplasm and accumulation in central nervous system [25]. Advancement in Lafora disease is due to mutation in Laforin protein as major cause of progressive myoclonic epilepsies. Table 4 shows the ligand-protein interaction map of target protein with ligands. 34

4 Sn.O Protein Target/PDB Id Table 4. ligand protein interaction map. Chemical Ligand-Protein Interaction Map Compound 1 3FI3 (JNK3) Pinostilbine 2 5HTB (Haspin) Resveratrol 35

5 3 4RKK (Laforin) Polydatin 4 3FV8 (JNK3) Pinostilbine 36

6 5 3FI2 (JNK3) Resveratrol 4. Conclusion Docking between proteins of progressive myoclonus epilepsy and antioxidants as ligands suggest that Resveratrol, Polydatin and Pinostilbine can be suitable antioxidants to treat PME. Ligand protein Interaction analysis shows that Pinostilbine and Resveratrol shows hydrogen bonds with JNK3 protein and can be potent antioxidants against JNK3 protein target. Whereas Polydatin and Resveratrol have strong interaction by hydrogen bonds with Laforin and Haspin protein. Further docking analysis proves that resveratrol can be potent antioxidant against progressive myoclonus epilepsy. References 1. Girard, Jean-Marie, et al. "Progressive myoclonus epilepsy." Handbook of clinical neurology. Vol Elsevier, Zupanc, Mary L., and Benjamin Legros. "Progressive myoclonic epilepsy." The Cerebellum 3.3 (2004): Satishchandra, P., and S. Sinha. "Progressive myoclonic epilepsy." Neurology India 58.4 (2010): Pennacchio, Len A., et al. "Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)." Science (1996): Chan, Elayne M., et al. "Mutations in NHLRC1 cause progressive myoclonus epilepsy." Nature genetics 35.2 (2003): Vilchez, David, et al. "Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy." Nature neuroscience (2007): Berkovic, Samuel F., et al. "Progressive myoclonus epilepsies: specific causes and diagnosis." New England Journal of Medicine (1986): Ganesh, Subramaniam, et al. "Recent advances in the molecular basis of Lafora s progressive myoclonus epilepsy." Journal of human genetics 51.1 (2006): Minassian, Berge A., et al. "Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy." Nature genetics 20.2 (1998): Singh, Shweta, and Subramaniam Ganesh. "Lafora progressive myoclonus epilepsy: A meta analysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes." Human mutation 30.5 (2009): Delgado-Escueta, Antonio V. "Advances in lafora progressive myoclonus epilepsy." Current neurology and neuroscience reports 7.5 (2007): Chan, E. M., et al. "Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22." Journal of medical genetics 40.9 (2003):

7 13. Vilchez, David, et al. "Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy." Nature neuroscience (2007): Ianzano, Leonarda, et al. "Lafora progressive myoclonus epilepsy mutation database EPM2A and NHLRC1 (EMP2B) genes." Human mutation 26.4 (2005): Chan, E. M., et al. "Progressive myoclonus epilepsy with polyglucosans (Lafora disease) Evidence for a third locus." Neurology 63.3 (2004): Pennacchio, Len A., et al. "Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1)." Science (1996): Minassian, Berge A., et al. "Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy." Nature genetics 20.2 (1998): Berman, Helen, et al. "The worldwide Protein Data Bank (wwpdb): ensuring a single, uniform archive of PDB data." Nucleic acids research 35. suppl_1 (2006): D301-D Butkiewicz, Mariusz, et al. "Benchmarking ligand-based virtual High-Throughput Screening with the PubChem database." Molecules 18.1 (2013): Schrodinger, L. "Schrodinger software suite." New York: Schrödinger, LLC 670 (2011). 21. Halgren, Thomas A., et al. "Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening." Journal of medicinal chemistry 47.7 (2004): Tian, Ye, Xu Han, and Da li Tian. "The biological regulation of ABCE1." IUBMB life (2012): Alonso, Andres, et al. "Protein tyrosine phosphatases in the human genome." Cell (2004): Malaspina, Andrea, Narendra Kaushik, and Jackie De Belleroche. "Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cdna arrays." Journal of neurochemistry 77.1 (2001): Bountra, Chas, Udo Oppermann, and Tom D. Heightman. "Animal models of epigenetic regulation in neuropsychiatric disorders." Molecular and Functional Models in Neuropsychiatry. Springer, Berlin, Heidelberg, /19/