Interaction Study of Antioxidants with Progressive Myoclonus Epilepsy by Molecular Docking Techniques

 

Ruchi Yadav, Prachi Srivastava*

Amity Institute of Biotechnology, Amity University, Lucknow, UP, India- 226028

 

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.

 

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.

Table 1 List of proteins involved in progressive myoclonus epilepsy

SN.O	UNIPROT ID	PROTEIN NAME	DISEASES	FUNCTION
1	095278	Laforin	Epilepsy progressive  myoclonic 2 (EPM 2)	Involved in the clearance of toxic polyglucosan and proteins aggregates via multiple pathways
2	P54098	DNA polymerase subunit gamma 1	progressive external opthalnoplagea with mitochondrial DNA deletion ,autosomal dominant	Involved in the replication of mitochondrial DNA
3	Q6VVB1	E3 ubiquitin protein ligase	Epilepsy progressive myoclonic 2 (epm 2)	Involved in clearance of toxic polyglucosan
4	P48553	Trafficking protein particle complex subunit 10	Nil	play a role in vesicular transport from endoplasmic reticulum to Golgi
5	P04080	Cystatin b	Epilepsy progressive myoclonic 1	Intracellular thiol proteinase inhibitor
6	Q13510	Acid ceradimise	Farber lipogranulomatosis(FRBR  L)	Hydrolysis of the sphingolipid ceramide
7	Q96mt3	Prickle like  protein 1	Epilepsy progressive myoclonic 1b(EPM 1B)	Involved in the planar cell polarity pathway
8	Q14653	Golgi SNAP receptor complex member 2	Epilepsy progressive myoclonic 6(epm 6)	Involved in transport of proteins from the cis mediated Golgi to the trans Golgi network
9	Q96mp8	BTB/POZ domain containing protein KCTDT	Epilepsy progressive myoclonic 3 with or without intracellular inclusions (EPM3)	Involved in the control of excitability of cortical neurons
10	P48547	Potassium voltage  gated channel sub family c memeber	epilepsy progressive myoclonic 7(EPM7)	Mediates the voltage dependent potassium ion
11	P27544	Ceramide synthase 1	Epilepsy progressive myoclonic 8(EPM 8)	Involved in the production of sphingolipids containing mainly one fatty acid donor
12	Q9WUA5	Laforin	Disrupts on phenotype	Impaired behavioural responses ataxia
13	Q03252	Lamin b 2	partial acquired lipodystrophy	Lamins are component of nuclear lamina
14	Q9NQV8	PR domain zinc finger protein b	Epilepsy progressive myoclonic 10(EPM 10)	Involved in the control of steroidogenesis
15	Q716J9	splicing endonuclease subunit	Pontocerebellar-hypoplasia 4(PCM 4)	A complex is responsible for identification and cleavage of the splices site in pre tRNA
16	Q713G6	Prickle like protein 2	Spinocerebellar ataxia with epilepsy (SCAE)	Zinc ion binding

 

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].

 

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 -3451

2.   5HTB:

Crystal structure of haspin (GSG2) in complex with substrate inhibitor ARC 3353.

 

3.   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 p38

 

2.2 Ligands:

Antioxidants are selected from Pubchem database [19]. Ten ligands files were downloaded 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

SNO	PUBCHEM ID	LIGAND NAME	MOLECULAR FORMULA
1	3676	LIDOCAINE	C14H22N2O
2	21910	EPIPROPIDINE	C16H28N2O2
3	53510	RES 2664	C25H22BrNO
4	445154	RESVERATROL	C14H12O3
5	637098	MAXIMOL A	C28H22O6
6	5281718	POLYDATIN	C20H22O8
7	5473050	PINOSTILBINE	C15H14O3
8	10475251	RES-1149-1	C23H30O5
9	100920621	GNETIN C	C28H22O6
10	100944900	PTEROSTILBENE	C32H30O6

 

2.2 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

Table 3 Docking scores of ligand with protein

Protein/ Ligands	Lidocaine	Epipropidine	Res 2664	Resveratrol	Maximol A	Polydatin	Pinostilbine	Res-1149-1	Gnetin C	Pterostilbene
3FI3	-6.72	-5.996	-6.983	-8.255	-6.486	-7.716	-8.522	NA	-6.968	-3.151
5HTB	-3.04	-3.026	-3.664	-4.385	NA	-3.782	-3.789	-2.856	-2.06	NA
4RKK	-3.91	-4.525	-3.529	-6.308	-5.642	-7.054	-5.561	-5.155	-4.985	NA
3FV8	-5.02	-5.109	-5.552	-8.253	-6.34	-8.368	-9.122	-7.332	-5.529	NA
3FI2	-5.75	-5.967	-7.277	-8.923	-4.971	-8.024	-8.212	NA	-6.428	-5.022

 

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.

 

Table 4 ligand protein interaction map .

S. No	Protein Target/PDB Id	Chemical Compound	Ligand-Protein Interaction Map
1	3FI3 (JNK3)	Pinostilbine
2	5HTB (Haspin)	Resveratrol
3	4RKK (Laforin)	Polydatin
4	3FV8 (JNK3)	Pinostilbine
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.

 

5. CONFLICT OF INTEREST:

The Author(s) declare(s) that there is no conflict of interest’.

 

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