Abstract
Self-assembly of phenylalanine creates Phe fibers which is the characteristic fiber model found in amyloid fibrils linked with various neurodegenerative diseases. L-Isoleucyl-L-Phenylalanine (Ile-Phe) dipeptide is composed of isoleucine and phenylalanine amino acids, having fibrillary structure similar to nanotube forms of the core recognition motif of Alzheimer's β-amyloid polypeptide. The integrated coordination of neuronal responses via the PI3-K / Akt pathway has a significant functional impact on Alzheimer's disease. Exposure to Aβ in neuronal cultures leads to deterioration of PI3-K, Akt and mTOR signaling, which may cause cognitive loss during disease. Modulation of PI3-K, Akt and mTOR signal activity need aim to reduce or eliminate the accumulation of potential neurotoxins. The therapeutic approaches aimed to normalize neuronal responses on these pathways or activation of PI3-kinase have a protective effect against cognitive decline in animal models of Alzheimer disease. This study aims to determine the interaction of PI3-kinase with Ile-Phe dipeptide having amyloid fibril structure by three-dimensional simulation techniques such as molecular dynamics (with the GROMACS program) and molecular docking techniques (Schrodinger Software program).
Highlights
Protein misfolding and accumulation of amyloid aggregates are the leading causes of a wide variety of diseases including multiple neurodegenerative disorders such as Alzheimer's disease (Wolfe & Cyr, 2011)
The Ile-Phe dipeptide, which consist of Phe residue, having fibrillar structure form are similar to nanotube forms that the core recognition motif (Phe-Phe) of β-amyloid polypeptide
The aim of this study is to elucidate by using the molecular docking technique the mechanism of interaction between Ile-Phe dipeptide which is an amyloid-like peptide molecule structure and Phosphoinositol 3-kinase (PI3K)/Akt receptor for better understanding the pathogenesis of Alzheimer's disease
Summary
Protein misfolding and accumulation of amyloid aggregates are the leading causes of a wide variety of diseases including multiple neurodegenerative disorders such as Alzheimer's disease (Wolfe & Cyr, 2011). Amyloid-β (Aβ) in the brain tissues and cerebral vessels of Alzheimer's patients accumulates as plaques, leading to impaired neurovascular function and chronic neurodegeneration have numerous toxic effects on neurons, astrocytes, glial cells and brain endothelium (Turkseven, 2014). The PI3K / Akt pathway functions as neuroprotective agents that inhibit neuronal apoptosis (Kitagishi et al, 2014). Defective Aβ protein metabolism and many different biochemical pathways including inflammatory, oxidative and hormonal pathways can trigger Alzheimer's disease. The evaluation of all these pathways has a significant potential for disease prevention and treatment. (Kitagishi et al, 2014)
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