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Namrata Singh

Namrata Singh

Associate Professor, DY Patil University, India

Title: Assessment of binding interactions of Alzheimer’s drug candidates with Bovine Serum Albumin

Biography

Dr. Namrata Singh received her Ph. D degree from Pt. Ravishankar Shukla University, Raipur, India, in 2013 in physico-organic chemistry with Prof. Kallol K. Ghosh. Her thesis research interests were surfactants, micellar kinetics and oxime based AChE reactivators. She worked for two years as postdoctoral-scientist with Prof. Zdeněk Fišar at first faculty of medicine, Charles University in Prague, Czech Republic and studied the genetic, biological and environmental factors of mental disorders especially cognitive enhancers and mitochondrial functions. In 2015 she joined Department of chemistry, Indian Institute of Technology, Bombay as postdoctoral fellow to study drug-protein interactions and their biothermodynamics. She is currently working as Assistant Professor at Department of Engineering Sciences, DY Patil’s Ramrao Adik Institute of Technology, Mumbai. Her current research interests include neurodegenerative disorders particularly Alzheimer’s disease, cannabinoids and mitochondrial respiration, cholinesterase inhibitors, bio-thermodynamics of drug-protein, drug-surfactant and drug-drug interactions. She has published seventeen research articles, one short communication, one book chapter and four review articles in journals of high repute. She has bagged prestigious scientific awards and recognitions including Young Scientist Awards and national and international research fellowships. She is interested in physicochemical and biochemical aspects of drugs for neurodegenerative disorders. Currently her research interests include drug-protein interactions and aggregation/fibrillation of proteins.

 

Abstract

Statement of the Problem: The pharmacokinetics and pharmacodynamics of a drug can be well understood and interpreted by measuring the extent of drug binding to plasma proteins.  Reliability of a protein-protein interaction model specific to Alzheimer’s disease (AD), can lead to screening, and prioritization of novel protein candidates [1]. Thus, the investigation of such molecules with respect to albumin binding is of imperative and fundamental significance. Methodology & Theoretical Orientation: Spectroscopic (UV-Visible absorption, steady-state fluorescence and circular dichroism) and calorimetric (isothermal titration calorimetry) techniques have been employed to investigate the interactions of water soluble novel Novel Alzheimer’s drug candidates (7-MEOTA-donepezil like compounds) with bovine serum albumins (BSA) under physiological conditions. Fluorescence quenching spectra in combination with circular dichroism (CD) spectroscopy was used to investigate the drug-binding mode, the binding constant and the protein structure changes. The apparent binding constants and number of substantive binding sites using site markers (warfarin and diazepam) have been evaluated by fluorescence quenching method. The thermal unfolding of BSA in absence and presence of drugs has been studied by CD spectroscopy. Findings: The drugs substantially quenched the intrinsic fluorescence of BSA. Synchronous fluorescence studies indicate the binding of selected Alzheimer’s drugs with BSA mostly changes the polarity around tryptophan residues rather than tyrosine residues. The circular dichroism studies indicate that the binding has induced considerable amount of conformational changes in the protein. However, calorimetric studies did not manifest drug-protein binding. Conclusion & Significance: Binding of the selected Alzheimer’s drug revealed static quenching mechanism through hydrogen bonds and van der Waal’s attraction. The thermodynamic parameters indicated that hydrophobic and electrostatic interaction played main role in the binding. An understanding of detailed energetic and mechanism of binding may be useful for providing safer and efficient therapies for Alzheimer’s disease and diagnoses in clinical settings as well [2]. A systematic review of attempts and achievements of such interactions has been done and future scope has been predicted. Outcomes for therapy with AD drugs already under clinical trials have been studied carefully and discussed.