Modelling Approach to Design The Structure of cln8 and Targeting it for Drug Binding, A Means to treat Epilepsy

Author Name: *Subhashree Hota, Pritam Kumar Panda, Suman Mishra, Samaya Chakra Pradhan, Biswajit Satapathy, Piyus Pritam
Author Email: mail2subhashree143@gmail.com

Abstract

Epilepsy is one of the genetic diseases that is existing from the past. Though it is less observed statistically, it has a very bad effect on the victim. There are several approaches to resolve certain symptoms of the disease. Drug targeting is one of the routinely used approaches for the same. The current work involves the study of the protein CLN8, one of the major causes of epilepsy. The Sequence, Structural and functional annotation of the protein was performed using several insilico tools. As the structure of the CLN8 protein is not available in the literature, the work included modeling approach using modeler to design the appropriate structure for the protein. The protein thus designed is validated and is used as a receptor in docking. The chemicals that can act against the complications of Epilepsy were screened from CHEBI and Pubchem. The selected chemicals were filtered according to their Druglikeliness, Toxicity and Ambiguity. The final list of selected chemicals was allowed to dock with the receptor using Hex Software followed by energy evaluation.

Keywords

Ceroid lipo fuscinosis neural 8(CLN8 Protien); Computational Analysis; Homology Modelling; Rasmol Drug Designing.

Introduction

EPILEPSY:
Epilepsy is a brain disorder in which clusters of nerve cells, or neurons, in the brain sometimes signal abnormally. Neurons normally generate electrochemical impulses that act on other neurons, glands, and muscles to produce human thoughts, feelings, and actions. In epilepsy, the normal pattern of neuronal activity becomes disturbed, causing strange sensations, emotions, and behaviour, or sometimes convulsions, muscle spasms, and loss of consciousness. During a seizure, neurons may fire as many as 500 times a second, much faster than normal. In some people, this happens only occasionally; for others, it may happen up to
hundreds of times a day. Epilepsy is not contagious and is not caused by mental illness or mental retardation. Some people with mental retardation may experience seizures, but seizures do not necessarily mean the person has or will develop mental impairment. Many people with epilepsy have normal or above-average intelligence. Famous people who are known or rumored to have had epilepsy include the Russian writer Dostoyevsky, the philosopher Socrates, the military general Napoleon, and the inventor of dynamite, Alfred Nobel, who established the Nobel Prize. Several Olympic medalists and other athletes also have had epilepsy. Seizures sometimes do cause brain damage, particularly if they are severe. However, most seizures do not seem to have a detrimental effect on the brain. Any changes that do occur are usually subtle, and it is often unclear whether these changes are caused by the seizures themselves or by the underlying problem that caused the seizures. The major gene having a vital role in epilepsy was found to be CLN8. CLN8 (ACCESSION NO: NP_061764). The official name of this gene is “ceroid-lipofuscinosis, neuronal 8 (epilepsy, progressive with mental retardation).”
NORMAL FUNCTION OF GENE: The CLN8 gene provides instructions for making a protein whose precise function is not known but is thought to play a transport role within cells. Specifically, the CLN8 protein likely helps to transport materials in and out of a cell structure called the endoplasmic reticulum, which is involved in protein production, processing, and transport. Based on the structure of the CLN8 protein, it may also be involved in regulating the levels of fats (lipids) in cells. Neuronal ceroid lipofuscinosis 8; CLN8 and Northern epilepsy : autosomal recessive inheritance, age of onset 2-7 years,clinically characterized by psychomotor deterioration, epileptic seizures, myoclonus, ataxia, loss of vision and premature death ,clinically characterized by psychomotor deterioration, epileptic seizures, myoclonus, ataxia, loss of vision and premature death,accumulation of characteristic storage material in cells ,Northern epilepsy: an allelic disorder caused by a Finnish founder mutation in CLN8; age of onset 5-10 years, characterized by progressive epilepsy and mental retardation, motor clumsiness, behavioral problems and a protracted disease course .

Conclusion

In the current work the major importance was given for the construction and validation of the protein structure by modeling using modeler approach. Once the structure was designed and optimized along with the quality evaluation, the structure was used for targeting with the selected ligand. To select the best drug for the receptor chemicals were collected from the PubChem and CHEBI databases. The collected chemicals were screened for the Drug likeliness, Toxicity and ambiguity check. The selected 5 chemicals were further used to dock with the pre designed receptor. After the docking analysis the evaluation of the energies was made based on which the best ligand selected was Parampanel hydrate with the e total of -263.48. The compound can be used as a drug for the treatment of epilepsy symptoms.

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