Presenatation on insillico drug design

Presenatation on insillico drug design

1. 1
Department of Pharmacology BVVS
COP BGK
PRESENATATION ON
INSILLICO DRUG
DESIGN

2. WHATAREDRUGS?
Achemicalsubstancethataffectstheprocessesofthe
mindorbodywhichisusedin
Diagnosis
Treatment
Preventionofdiseaseorotherabnormalcondition.
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Department of Pharmacology BVVS
COP BGK

3. 3
Department of Pharmacology BVVS
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4. DrugDesigning
Drugdesigning,istheinventiveprocessoffinding
newmedicationsbasedontheknowledgeofa
biologicaltarget.
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Department of Pharmacology BVVS
COP BGK

5. Drugdesigning…..
Selected/designedmolecule
shouldbe:
Organicsmallmolecule.
Complementaryinshapeto
thetarget.
Oppositelychargetothe
bio-moleculartarget.
5
Department of Pharmacology BVVS
COP BGK

6. Drugdesigning…..
Thismoleculewill:
interactwithtarget
bindtothetarget
activatesorinhibitsthefunctionofabiomolecule
suchasaprotein
6
Department of Pharmacology BVVS
COP BGK

7. INSILICODRUGDESIGNING
InSilicoisanexpressionusedtomean“performed
oncomputerorviacomputersimulation.”
InSilicodrugdesigningisdefinedasthe
identificationofthedrugtargetmoleculeby
employingbioinformaticstools.
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Department of Pharmacology BVVS
COP BGK

8. 8
Department of Pharmacology BVVS
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9. Ligandbaseddrugdesign
Ligand-baseddrugdesignrelies
onknowledgeofother
moleculesthatbindtothe
biologicaltargetofinterest
Usedtoderivea
pharmacophore
9
Department of Pharmacology BVVS
COP BGK

10. Structure based drug
design
Structure-based drug
design relies on
knowledge of the three
dimensional structure of
the biological target
obtained through methods
such as
x-ray crystallography
NMR spectroscopy.
homology modeling
10
Department of Pharmacology BVVS
COP BGK

11. Structure based drug design…..
Using the structure of the biological target, drugs
that are predicted to bind with to the target may be
designed using
interactive graphics
the intuition of a medicinal
chemist.
automated computational
procedures
11
Department of Pharmacology BVVS
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12. Basic Steps In In SilicoDrug Designing
12
Department of Pharmacology BVVS
COP BGK

13. Selectionofdisease
Determinethebiochemicalbasisofthedisease
process.
Knowtheexactstep(s)inthepathwaythatare
alteredinthediseasedstate.
Knowledgeabouttheregulationofthepathwayis
alsoimportant.Finally,onewouldknowthethree-
dimensionalstructuresofthemoleculesinvolvedin
theprocess.
13
Department of Pharmacology BVVS
COP BGK

14. Targetselection
Biochemicalpathwayscouldbecomeabnormaland
resultindisease.
Selectatargetatwhichtodisruptthebiochemical
process.
Categoriesoftargets
Targetformechanisticdrugdesignusuallyfallinto
threecategory:
enzymes
receptors
nucleicacids.
14
Department of Pharmacology BVVS
COP BGK

15. TargetValidation:
PerformtheproteinBLASTforallthegenes/proteins
withrespecttoHomosapiens.
Selecttheleastmatchingmoleculeinhumanand
againperformtheBLAST.
Asthequerysequencematchedbest,soweselected
ourtargetmoleculeanditsstructurecanbeobtained
fromRCSB(TheResearchCollaborationforStructural
Bioinformatics)PDB(ProteinDataBank).
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Department of Pharmacology BVVS
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16. Selectionofligands/drugs
AlsocalledasLeadIdentification
Highthroughputscreeningofnaturalproductand
syntheticcompoundlibrariesiscarriedtoscreenout
leadcompound.
16
Department of Pharmacology BVVS
COP BGK

17. Criteria to be fulfilled…..
17
Department of Pharmacology BVVS
COP BGK

18. Scoring
ScoringfunctionsQuantifytheenergyofprotein/ligand
interactionssuchas:
Hydrogenbond
Electrostatics
Hydrophobic
Lead Optimization
Refining the 3D structure of the lead compounds.
Technique used is QSAR.
18
Department of Pharmacology BVVS
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19. PreclinicalandClinicalDevelopment
19
Department of Pharmacology BVVS
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20. CONCLUSION
Intheselectionofnewdrugcandidates,manyefforts
arefocusedontheearlyeliminationofcompounds
thatmightcauseseveralsideeffectsorinteractwith
otherdrugs.Insilicotechniqueshelpinthisregard
andtheyaregoingtobecomeacentralissueinany
rigiddrugdiscoveryprocess.
Insilicotechnologyalonecannotguaranteethe
identificationofnew,safeandeffectivelead
compoundbutmorerealisticallyfuturesuccess
dependontheproperintegrationofnewpromising
technologieswiththeexperienceandstrategiesof
classicalmedicinalchemistry.
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Department of Pharmacology BVVS
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Department of Pharmacology BVVS
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22. Introduction
Ahitisacompoundwhichhasthedesiredactivityin
acompoundscreenandwhoseactivityisconfirmed
uponretesting.
Leadcompoundsarechemicalcompoundsthatshow
desiredbiologicalorpharmacologicalactivityand
mayinitiatethedevelopmentofanewclinically
relevantcompound.
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Department of Pharmacology BVVS
COP BGK

23. Processofhitidentification:
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Department of Pharmacology BVVS
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24. Hitidentification:
Forhitidentification,someinformationabouteither
thetargetproteinoranactivecompoundis
necessary.
Inthecaseofaknownstructureoftheprotein,a
virtualscreeningofcompoundlibrariesleadsto
virtualhitswhichwillbesynthesisedandtested
afterwardsortestedimmediately.
Ifthestructureofthenaturalsubstrateisknown,a
ligandbasedapproachwillbeaccomplished.
Thecomputersearchesforsimilarcompoundsand
theresultinghitsarecheckedfordruglike
properties.
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Department of Pharmacology BVVS
COP BGK

25. HitIdentificationAssayFeatures
Proteintargetcanbemembranebound,difficultto
produceforstandardbiochemicalassays,and
difficulttopurify;
Hitandleadcompoundsandfocusedlibrariescanbe
screenedagainstproteintargetwithinphysiological
environment;
Compound cellpermeability,specificityand
cytotoxicityareassessedinoneprocess;
Processcanbeupscaledtoscreenhundredsof
compoundsinafewhours.
25
Department of Pharmacology BVVS
COP BGK

26. Assaydevelopment:
Assaydevelopmentoneofthefirststepsindrug
developmentandtoxicitytestingiscreatingtest
systems(assays)onwhichtoevaluatetheeffectsof
chemicalcompoundsoncellular,molecularor
biochemicalprocessesofinterest.
Intherecombinanterathemajorityofassaysinuse
withintheindustryrelyuponthecreationofstable
mammaliancelllinesover-expressingthetargetof
interest,or
Upontheover-expressionandpurificationof
recombinantproteintoestablishso-called
biochemicalassays.
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Department of Pharmacology BVVS
COP BGK

27. Cont..
Cell-basedassayshavebeenappliedtotargetclasses
suchasmembranereceptors,ionchannelsand
nuclearreceptors.
Incontrast,biochemicalassays,whichhavebeen
appliedtobothreceptorandenzymetargets,often
simplymeasuretheaffinityofthetestcompoundfor
thetargetprotein.
Thechoiceofassayformatisdependentuponthe
biologyofthedrugtargetprotein,theequipment
infrastructureinthehostlaboratory,theexperience
ofthescientistsinthatlaboratory,whetheran
inhibitororactivatormoleculeisreceiveandthe
scaleofthecompoundscreen.
27
Department of Pharmacology BVVS
COP BGK

28. Cont…
ForexamplecompoundscreeningassaysatGPCRs
havebeenconfiguredtomeasurethebindingaffinity
ofaradio-orfluorescentlylabelledligandtothe
receptor,
Tomeasureguaninenucleotideexchangeatthelevel
oftheGprotein,
Tomeasurecompound-mediatedchangesinoneofa
numberofsecondmessengermetabolitesincluding
calcium,cAMPorinositiolphosphates.
HitIdentificationAssayApplications
Targetidentificationorvalidationforhitphenotypic
screening.
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Department of Pharmacology BVVS
COP BGK

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Department of Pharmacology BVVS
COP BGK