satpathy_flu

8/7/2019 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



ContentsContents

IntroductionIntroduction

Materials and methodsMaterials and methods

Results and discussionResults and discussion

ConclusionConclusion



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



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



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



Common DrugsCommon Drugs

Two FDA approved drugsTwo FDA approved drugs

Zanamivir Zanamivir andand Oseltamivir Oseltamivir both areboth are

neuraminidase inhibitorsneuraminidase inhibitors



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



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



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



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



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



Docking studyDocking study

Drug and protein:

Lock and key mechanism,

blocking=>stopping of protein

function



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



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.



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%)



Structure of modelStructure of model



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



MODEL VALIDATIONMODEL VALIDATION

(DOPE SCORE)(DOPE SCORE)



MODEL VALIDATIONMODEL VALIDATION

(ERRAT AND PROCHECK)(ERRAT AND PROCHECK)



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



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.



Docking with ZANAMIVIR andDocking with ZANAMIVIR and

analogsanalogsDrugs docked E -valuesZanamivir -207.88

Zanamivir analog 1 -205.81












Docking with Oseltamivir andDocking with Oseltamivir and

analogsanalogsDrugs docked E -values

Oseltamivir -193.53

Oseltamivir analog 1 -195.58


Oseltamivir analog 3 -198.22Oseltamivir analog 4 -198.83




Oseltamivir analog 8 -231.21Oseltamivir analog 9 -209.74




Zanamivir and analog 10Zanamivir and analog 10

((--CHCH22OCHOCH22CHCH22OH)OH)



Oseltamivir and analog 8Oseltamivir and analog 8

((--CHCH22COOH GROUPCOOH GROUP))



Docking of Docking of Oseltamivir Oseltamivir andand analog 8analog 8



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..



NEXT «NEXT «

QSAR analysisQSAR analysis

Molecular assembly thatMolecular assembly thatinteracts with the druginteracts with the drug

activityactivity



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