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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.