Analysis and targeting of NRG1 protein via in-silico Drug Design approach (Structure based) for the treatment of Schizophrenia

Author Name: Anuja Srivastava
Author Email: anuja.vbiotech1406@gmail.com

Abstract

Neuregulin-1 (NRG-1) is a gene that helps regulate synaptic plasticity and mutations in NRG-1 have been found in patients with schizophrenia. Researchers have found that the prefrontal cortex expresses much higher levels of NRG-1 in humans with schizophrenia. Researchers have found that the mice grown with over expression of NRG-1 had schizophrenia like symptoms which were controlled once the level was brought back to normal using the drug doxycycline. With the importance of the NGR-1 protein in nerve regeneration and functionality the current work involves the annotation and analysis of the protein. The work also includes targeting of the same protein to the screened chemicals for docking, a means to eradicate the symptoms of schizophrenia. The analysis includes the proteins physicochemical characterization using protparam, SMART and Prosite for domain analysis, SOPMA, CPH, PHYRE, etc for structure analysis. The proteins phylogeny was established by retrieving the related sequences from the other organisms using BLAST and establishing their relation based on CLUSTAL W dendrogram. The Protein structure was downloaded and optimized using Argus Lab for further docking studies. The chemicals capable of resolving the symptoms of neurological problems have been screened and selected from the PUBCHEM database. Once the selection of the chemicals was once after proper screening for Drug likeliness, Ambiguity and Toxicity the chemicals were also optimized. The optimized chemicals were used to dock with the receptor protein and the results were analyzed. Based on the lowest binding energy and high docking affinity the best chemicals were selected as the potential drugs for the receptor in the treatment of the disorder.

Keywords

Schizophrenia, NRG-1, Docking, Phylogeny, Domain Analysis.

Introduction

Schizophrenia is a chronic, severe and disabling brain disease. People with schizophrenia often suffer terrifying symptoms such as hearing internal voices not heard by others, or believing that other people are reading their minds, controlling their thoughts, or plotting to harm them. It is a neurological disorder with several protein and metabolic causes. One of the protein having its vital functional in neuronal development is Neuregulin the product of NRG-1 gene. The concentration of this protein in the brain is responsible for the proper functioning of the nervous system. An imbalance in its concentrations leads to the onset of disorders, one of which is schizophrenia. The symptoms of the disorder includes Alogia, Affective flattening, Avolition, disorganized thinking, slow thinking, difficulty understanding, poor concentration, poor memory, difficulty expressing thoughts and difficulty integrating thoughts, feelings and behavior. There are three major subtypes of schizophrenia, each classified by their most prominent symptom: paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia. Neuregulin 1 or NRG1 is a protein that in humans is encoded by the NRG1 gene. NRG1 is one of four proteins in the neuregulin family that act on the EGFR family of receptors. Neuregulin 1 is produced in numerous isoforms by alternative splicing, which allows it to perform a wide variety of functions. It is essential for the normal development of the nervous system and the heart. The alterations in the concentration or the functionality of this proteins leads to the onset of various neuregulinnal disabilities, one of which is the Schizophrenia. The treatment for the disease would be the alteration in the concentration of the protein.

Conclusion

NRG1 being a cause for schizophrenia has been selected in the current study. The Protein annotation and evolutionary study was performed. Using several tools the structural characterization was performed and the structure was collected from the PDB Database. Based on the structure binding site selection were performed using disorder prediction tools, Binding site and domain identification tools etc. The final site selected was MET22 position. Pubchem was used to select the chemicals and then were screened based on the various parameters like Drug likeliness, Toxicity, Ambiguity etc. Finally 4 chemicals listed above were selected and were docked with the receptor using PATCH DOCK software. Based on the docking scores the best chemical selected was piflutixol with the docking score of 4232. Thus it can be concluded that the chemical piflutixol can be used as a best drug against treating the symptoms of schizophrenia.

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