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Transcript of Satpathy_FLU
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Computational rational design of AntiviralComputational rational design of Antiviral
Drugs for Swine fluDrugs for Swine flu
ByBy
RaghunathRaghunath SatpathySatpathyMIRC LAB,MIRC LAB,MITS ENGINEERING COLLEGE ,MITS ENGINEERING COLLEGE ,
RAYAGADARAYAGADA
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ContentsContents
IntroductionIntroduction
Materials and methodsMaterials and methods
Results and discussionResults and discussion
ConclusionConclusion
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IntroductionIntroduction
Swine flu now becomes a deadestSwine flu now becomes a deadest
disease throughout the world.disease throughout the world.
Caused by 2009H1N1 virusCaused by 2009H1N1 virus
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Immunogenic Components of theImmunogenic Components of the
Influenza VirusInfluenza Virus
Surface glycoprotein, 15 hemagglutinin (HSurface glycoprotein, 15 hemagglutinin (H11--HH1515), nine), nine
neurominidases (Nneurominidases (N11--NN99))
HH11--HH33 and Nand N11NN22 established in humansestablished in humans
Influenza characterized by combination of H and NInfluenza characterized by combination of H and Nglycoproteinsglycoproteins
1917 pandemic1917 pandemic -- HH55NN11
2004 avian influenza2004 avian influenza -- HH55NN11
2009 H2009 H11NN11
Human response is specific to hemagglutinin andHuman response is specific to hemagglutinin and
neurominidase glycoproteinneurominidase glycoprotein
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STRATEGIES TO PREVENT FLUSTRATEGIES TO PREVENT FLU
COVER MOUTH AND NOSE WHENCOVER MOUTH AND NOSE WHEN
SNEEZINGSNEEZING
WASH HANDS FREQUENTLY WITH SOAPWASH HANDS FREQUENTLY WITH SOAP AND WATER OR ALCOHOL AND WATER OR ALCOHOL
AVOID TOUCHING EYES, NOSE AND AVOID TOUCHING EYES, NOSE AND
MOUTHMOUTH
AVOID CONTACT WITH SICK PEOPLE AVOID CONTACT WITH SICK PEOPLE
TAKETAKE ANTIVIRAL DRUGS ANTIVIRAL DRUGS IF PHYSICIANIF PHYSICIAN
RECOMMENDSRECOMMENDS
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Common DrugsCommon Drugs
Two FDA approved drugsTwo FDA approved drugs
Zanamivir Zanamivir andand Oseltamivir Oseltamivir both areboth are
neuraminidase inhibitorsneuraminidase inhibitors
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BACKGROUNDBACKGROUND
A recent report says that currently isolates A recent report says that currently isolates
of Hof H11NN11 virus are resistant to presentlyvirus are resistant to presently
used neuraminidase inhibitor drugs likeused neuraminidase inhibitor drugs like
Zanamivir and Oseltamivir Zanamivir and Oseltamivir
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objectiveobjective11)To)To understandunderstand atat thethe molecular molecular levellevel howhow thisthis newnew
HH11NN11 virusvirus cancan bebe inhibitedinhibited byby thethe currentcurrent antianti--
influenzainfluenza drugsdrugs
22)Homology)Homology modelingmodeling of of aa (selected)(selected) neuraminidaseneuraminidaseproteinprotein
33)Docking)Docking withwith currentcurrent drugsdrugs likelike Zanamivir Zanamivir andand
Oseltamivir Oseltamivir
44)From)From dockingdocking resultresult findfind outout thethe molecular molecular partpartinvolvesinvolves inin thethe bindingbinding processprocess
55)Modification)Modification inin drugdrug moleculemolecule toto enhanceenhance thethe
bindingbinding processprocess
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Materials and methodsMaterials and methods
TheThe sequencesequence of of aa selectedselected neuraminidaseneuraminidase
enzymeenzyme waswas retrievedretrieved fromfrom NCBINCBI havinghaving
ACESSION ACESSION NONO.. GQGQ232095232095
TemplateTemplate structurestructure waswas derivedderived byby PDBPDB--BLASTBLAST
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Homology Modeling: How itHomology Modeling: How it
worksworks
o Find template
o Align target sequence
with template
o Generate model:- add loops
- add side chains
o Refine model
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Homology modelling (MODELLER)Homology modelling (MODELLER)
Constraints are
Homology derived constraints
Distances and angles between
aligned positions should be similar Stereochemical constraints
Bond lengths, bond angles,
dihedral angles, nonbonded atom-
atom contacts
Model are derived by minimizing restraints
Modeller: Sali & Blundell (1993
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Docking studyDocking study
Drug and protein:
Lock and key mechanism,
blocking=>stopping of protein
function
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What is ProteinWhat is Protein--LigandLigand Docking?Docking?
Definition:
Computationally predict the structures of
protein-ligand complexes from their conformations and orientations. The
orientation that maximizes the interaction
reveals the most accurate structure of the
complex.Importance of complexes
- structure -> function
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Docking studiesDocking studies
DOCKING WAS PERFORMED BY HEX 5.1
TOOLH ex calculates the protein-ligand docking,
assuming the ligand is rigid, and it can
superpose pairs of molecules using only
knowledge of their 3D shapesThe superpostion program to use spherical
polar Fourier (SPF) correlations to accelerate
the calculations.
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ResultsResults
The sequence for theneuraminidase protein having 468
amino acid was obtained from
NCBI having accession number gq232095.
Template 3cyeE-value (0.0),
identity (88%)
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Structure of modelStructure of model
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Structural details of the modelStructural details of the model
STRUCTURAL FEATURES INFORMATION
No. of residues 468
No. of atoms 3616
No. of Hydrogen bonds 252
No. of helices 3
No. of sheets 42
No. of turns 60
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MODEL VALIDATIONMODEL VALIDATION
(DOPE SCORE)(DOPE SCORE)
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MODEL VALIDATIONMODEL VALIDATION
(ERRAT AND PROCHECK)(ERRAT AND PROCHECK)
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DOPEDOPE,, or or DDiscreteiscrete OOptimizedptimized PProteinrotein EEnergy, is anergy, is a
statistical potentialstatistical potential used to assessused to assess homology modelshomology models
inin protein structure predictionprotein structure prediction & it generates a& it generates a
residueresidue--byby--residue energy profile for the input modelresidue energy profile for the input model ERRATERRAT (QUALITY FACTOR 64.8)(QUALITY FACTOR 64.8)
PROCHECKPROCHECK
% residues in favorable regions 81.7
% residues in additional residueregions
15.5
% residues in generously regions 1.3
% residues in disallowed regions 1.5
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Docking studyDocking study
Docking was performed by HEXDocking was performed by HEX 55..11 tooltool
with the model neuraminidase andwith the model neuraminidase and
original drug molecule viz.original drug molecule viz. Oseltamivir Oseltamivir andand
Zanamivir Zanamivir..
Docking by making different analogs(byDocking by making different analogs(by
MARVIN SKETCH toolMARVIN SKETCH tool ) of the above drug) of the above drug
molecules.molecules.
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Docking with ZANAMIVIR andDocking with ZANAMIVIR and
analogsanalogsDrugs docked E -valuesZanamivir -207.88
Zanamivir analog 1 -205.81
Zanamivir analog 2 -202.92
Zanamivir analog 3 -215.49
Zanamivir analog 4 -204.48
Zanamivir analog 5 -203.74
Zanamivir analog 6 -206.54
Zanamivir analog 7 -217.52
Zanamivir analog 8 -212.19
Zanamivir analog 9 -222.02
Zanamivir analog 10 -228.44
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Docking with Oseltamivir andDocking with Oseltamivir and
analogsanalogsDrugs docked E -values
Oseltamivir -193.53
Oseltamivir analog 1 -195.58
Oseltamivir analog 2 -201.36
Oseltamivir analog 3 -198.22Oseltamivir analog 4 -198.83
Oseltamivir analog 5 -207.61
Oseltamivir analog 6 -208.03
Oseltamivir analog 7 -229.53
Oseltamivir analog 8 -231.21Oseltamivir analog 9 -209.74
Oseltamivir analog 10 -224.83
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Zanamivir and analog 10Zanamivir and analog 10
((--CHCH22OCHOCH22CHCH22OH)OH)
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Oseltamivir and analog 8Oseltamivir and analog 8
((--CHCH22COOH GROUPCOOH GROUP))
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Docking of Docking of Oseltamivir Oseltamivir andand analog 8analog 8
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ConclusionConclusion
DockingDocking resultsresults indicateindicate thatthat thethe analoganalog 88 inin casecase of of
Oseltamivir Oseltamivir andand analoganalog 1010 inin casecase of of Zanamivir Zanamivir showshow
moremore potentpotent bindingbinding activityactivity thanthan thethe originaloriginal drugs,drugs,
thisthis correspondscorresponds toto inhibitioninhibition activityactivity againstagainst thethe viralviral
neuraminidaseneuraminidase..
ThisThis typetype of of analysisanalysis showshow thatthat thethe somesome of of thethe
modifiedmodified drugsdrugs havinghaving moremore potentialpotential activityactivity thanthan thethe
originaloriginal oneone maymay bebe usedused asas probableprobable leadlead moleculemolecule..
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NEXT «NEXT «
QSAR analysisQSAR analysis
Molecular assembly thatMolecular assembly thatinteracts with the druginteracts with the drug
activityactivity
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TTHHAANNKK Y YOOUU