e-ISSN: 2582-5208 International Research Journal of Modernization in Engineering Technology and Science Volume:02/Issue:12/December -2020
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COMPUTER-ASSISTED DRUG DESIGN OF DONEPEZIL ANALOGUES FOR ALZHEIMER’S DISEASE Sai Lakshmi.Palla*1, N.Dugnath*2, Manoj Kumar Mahto*3 *1,2,3 N.
Duganath, Department of Pharmaceutical Chemistry, Oil Technological Research Institute, Jawaharlal Nehru Technological University, Anantapur, Andhra Pradesh, India515001.
ABSTRACT Alzheimer's disease is a progressive disorder that causes brain cells to degenerate and die. Alzheimer’s disease is characterized by loss of neurons and synapses in the cerebral cortex and certain sub cortical regions. Alzheimer's disease is the most common cause of dementia a continuous decline in thinking, behavioral and social skills that disrupts a person's ability to function independently. Donepezil inhibit the acetylcholinesterase which degrades the acetylcholine transmitter. Computer Assisted Drug designing is used for the introduction of new therapeutic analogues of Donepezil. Energy minimization for analogues is done by using hyperchem software. Docking of the protein-ligand complex was done by using GOLD software. Present study includes new lead identification for Alzheimer’s disease, inhibiting the function of Acetyl cholinesterase protein, molecular docking studies. Binding affinity calculations by using molecular docking studies including computer aided drug design followed by molecular mechanics based binding affinity calculations. Keywords: Donepezil, Acetylcholinesterase, Binding affinity, Molecular docking, Molecular mechanics.
I.
INTRODUCTION
Bioinformatics is a management information system for molecular biology. Applications of Bioinformatics involve sequence analysis, molecular evolution, genome mapping database query tools and comparison, gene identification, structure prediction, drug designing and drug target identification. Computerassisted drug design (CADD), also called computer-assisted molecular design (CAMD) and represents more recent applications of computers as tools in the drug design process. In most current applications of CADD, attempts are made to find a ligand (the putative drug) that will interact favorably with a receptor that represents the target site. Binding of Ligand to the receptor may include hydrophobic, electrostatic, and hydrogen-bonding interactions. Ligand based drug design is applicable when the structure of the receptor site is unknown, but when a series of compounds have been identified that exert the activity of interest. Receptor based drug design1 incorporates several molecular modeling techniques, one of which is docking. Docking allows scoring based on force fields, which include both Vander Waals and electrostatic interactions. These results illustrate the potential for docking programs to search objectively for ligand than are complementary to receptor sites, thereby assisting researchers in identifying potential drugs than may be considerably different from existing drugs. The term molecular mechanics refer to the use of Newtonian mechanics to model molecular systems. Molecular mechanics have properties like each atom is stimulated as a single particle, each particle is assigned a radius, polarizability and constant net charge. MM+ is designed to reproduce the equilibrium covalent geometry of molecules as precisely as possible. AMBER is a family of force fields for molecular dynamics. The standard AMBER force field is parameterized to small organic constituents of proteins and nucleic acids. Energy minimization2 methods can precisely locate minimum energy conformations by mathematically “homing in” on the energy function minima.
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