Mechanistic Insights into Interaction of Alzheimers Drug with Proteins: A Biophysical Approach to Solve Neurodegenerative Diseases
Abstract
Asimul Islam
Neurodegenerative diseases affects more than 50 million elderly people worldwide with an associated health care cost of approximately $ 2000 billion per year. Parkinson's disease (PD) and Alzheimer's disease (AD) are linked with high brain iron accumulation relative to the amount of ferritin. Transferrin family is a group of proteins that function in the transport of iron around the blood stream after forming an iron-protein complex. AD is characterized by the presence of amyloid plaques (insoluble deposits of a 4 kDa peptide of ~ 40–42 amino acids in length) which is the leading causes of dementia in humans. Deposition of amyloid β plaques is a characteristic feature of Alzheimer’s disease and it is this event that leads to neuronal degeneration and cognitive decline. In earlier days, AD was thought of as untreatable condition but with recent advancements, Donepezil, a highly selective and reversible inhibitor, is amongst the widely used drugs for treatment of Alzheimer’s disease (AD) across the globe. Clinically significant human transferrin (hTf) is a key player involved in iron metabolism. The current study investigates into the interaction between donepezil and this plasma protein, hTf using UV-vis absorbance, fluorescence, isothermal titration calorimetry, circular dichroism and molecular docking techniques. The mechanism of binding and analysis of conformation of hTf complexed with donepezil were investigated at the molecular level under physiological conditions. Fluorescence spectroscopy clearly revealed occurrence of quenching in the fluorescence intensity of hTf in the presence of donepezil. Measurements of fluorescence at three different temperatures yielded values of binding constant and number of binding sites. Values of binding constant for hTf-donepezil interaction at 303 K and 310 K respectively are 0.007 X 104 M-1 and 1.3 X 104 M-1, implying the strength of this interaction. The negative value of �??G⁰ clearly revealed the formation of hTf-donepezil complex to be spontaneous and thermodynamically favorable. ITC gave an insight into this interaction and showed it to be thermodynamically favorable. Changes in far-UV CD spectrum of hTf in the presence of donepezil further confirmed the complex formation between hTf and donepezil. Molecular docking analysis gave an insight of the specific residues involved in hTf-donepezil interaction. This study gives an insight into the binding of an important Alzheimer’s drug, donepezil, with important plasma proteins, thereby giving new prospects and directions to the field of clinical medicine. mp3download.link Best YouTube to MP3 converter. Download MP3 from YouTube for Free. one would honestly have expected more on the track mp3-go.net Download Mp3 songs for free Given the legendary pedigree of the man behind the sound downloadmp3-gratis.biz Download mp3 songs online at Mp3 Converter, watch high quality online music videos download-mp3gratis.me watch and download free songs of the highest quality. Listen to songs online here comfortably without any annoying advertisements. metrolagu.com Easy to use and free MP3 downloader. YouTube To MP3 download in seconds using the best YouTube to MP3 converter. YouTube Mp3 Get the latest song by simply typing the latest artist or song title in the Search menu. Mp3 file format with 128 - 320 Kbps bitrate converted from YouTube videos. read at this blog All those artist performances are still available on YouTube today find more here
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