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Introduction
Cyclooxygenase2 (cox-2), a protein acts as an enzyme andspecifically catalyzes the production of certain chemical messengers
known as Prostaglandins.
The enzyme contains two active sites, A heme with peroxidase
activity responsible for reduction Of Prostaglandins G2 (PGG2) toPGH2 and a cyclooxygenase site where arachidonic acid is
converted into hydroproxy Endoperoxide Prostaglandins (PGG2).
COX enzyme exists in three isoforms - COX-1, COX-2 and COX-3.
Therefore, selective COX-2 inhibition would reduce the undesired
side effects such as gastro-intestinal disorders, ulcers and renal
failure.
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Objective
To find out a computer generated three dimensional molecular
homology model of Cox-2 protein and Docking with drug
candidate.
QSAR based approach for generation and optimization of
novel molecular leads.
An interaction between Cox-2 protein with optimized novel
drug candidate to find out the potent anti-cancerous drug for prevention of cancer in Human.
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MATERIALS ANDMETHODSProtein 3-D Structure Prediction:
Homology
Modeling
Model Building
BLAST
Protein Databank (PDB)
Modeller
Evaluation ofModel
Procheck
Ghost script viewer
Ligand Preparation
PubchemCompound
Chemscketch
Docking of flexible ligands to receptor
Autodock 3.0.5
AutoDock Tools
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3D QSAR-(quantitative
structure activity relationship)
3D-QSARrefers to the application of force field calculations
requiring three-dimensional structures, based on protein
crystallography or molecule superposition.
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HomologyModeling
Homology modeling predicts protein structures based on sequence
homology with known structures. It is also known as comparative
modeling.
The overall homologymodeling procedure consists of seven steps.
Template Selection
Sequence Alignment
Backbone Model Building
Loop Modeling
Side Chain RefinementModel Refinement Using Energy Function
Model Evaluation
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Model Building
The amino acid sequence of Cox-2 in Homo sapiens will be as atarget protein sequence. The modeling of 3D structure of target
protein followed a stepwise procedure.
BLAST : which finds regions of local similarity between sequences.
Protein Databank (PDB): is the repository for 3-D structure data
of proteins and nucleic acid.
Modeller : is a tool used for homology or comparative modeling of
protein three-dimensional structures
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Evaluation ofModel
Procheck is the program to check the stereo chemical quality of the
given protein structure, as compared with well refined structures.
Ghost script viewer is an interpreter for the PostScript (TM)
language.
Ligand Preparation : The chemical structures of cox-2 inhibitorswill be searched and retrieve from NCBI Pubchem compound
database and scientific literature.
PubchemCompound :database contains validated information
about the chemical structure of a compound.
Chemscketch : This software is designed for either online use or
to be printed and used as hardcopy version.
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Docking of flexible ligands to receptor
Autodock 3.0.5 : AutoDock [16] is a suite of docking tools. It isdesigned to predict how small molecules, such as substrates or
drug candidates, bind to a receptor of known 3D structure.
AutoDock Tools : AutoDock Tools, or ADT, is the free GUI forAutoDock developed by the same laboratory that develops
AutoDock.
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y In the late 1990s, the first COX-2 selective NSAIDCelebrex,was developed, and others soon followed.
y Theoretically, drugs which were developed asinhibitors were Celebrex,Vioxx, and Bextra shouldhave been preferred over traditional NSAIDs.
y Traditional NSAIDs ,ibuprofen, naproxen, however,can cause gastrointestinal problems including ulcers.
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y Other targets besides COX-2 are important for celecoxibsanticancer effects has come from studies with chemicallymodified versions of celecoxib.
y Several dozen analogs of celecoxib were generated withsmall alterations in their chemical structures.
y One of these compounds, 2,5-dimethyl-celecoxib, whichentirely lacks the ability to inhibit COX-2, display strongeranticancer activity than celecoxib.
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y The population of India is now over a billion with an
estimated 1.5 million cases of cancer diagnosed peryear.
y The population of the United States is 295 million,and yet 1.5 million cancers will be diagnosed this year..
y in US, prostate cancer accounts for 690 cases/million,while in India, it is 20/million.
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NON STEROIDAL ANTI INFLAMMATORY DRUGS
y Nonsteroidal anti-inflammatory drugs work byinterfering with the cyclooxygenase pathway.
yThe normal process begins with arachidonic acid, adietary unsaturated fatty acid obtained from animalfats.
y This acid is converted by the enzyme cyclooxygenase
to synthesize different prostaglandins.