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ComputerAidedDrugDesignppt
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HanumantSuryawanshi,Bioinformatician
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PublishedonMay9,2012

Publishedin:Education,Technology

ComputerAidedDrugDesignppt
1.Mr.HanumantSuryawanshiSchoolofTechnologySwamiRamanandTeerthMarathwadaUniversitySub
Center,Latur(Maharashtra)
2.Chapter1DrugDesign
3. Drug Achemicalsubstancethataffectstheprocessesofthemindorbody. Anychemical
compoundusedinthediagnosis,treatment,orpreventionofdiseaseorotherabnormalcondition. A
substanceusedrecreationallyforitseffectsonthecentralnervoussystem,suchasanarcotic.
4. Drugdesign,sometimesreferredtoasrationaldrugdesignormoresimplyrationaldesign,isthe
inventiveprocessoffindingnewmedicationsbasedontheknowledgeofabiologicaltarget. Thedrugis
mostcommonlyanorganicsmallmoleculethatactivatesorinhibitsthefunctionofabiomoleculesuchasa
protein,whichinturnresultsinatherapeuticbenefittothepatient.Inthemostbasicsense,drugdesign
involvesthedesignofsmallmoleculesthatarecomplementaryinshapeandchargetothebiomolecular
targetwithwhichtheyinteractandthereforewillbindtoit.Drugdesignfrequentlybutnotnecessarilyrelies
oncomputermodelingtechniques. Thistypeofmodelingisoftenreferredtoascomputeraideddrug
design.Finally,drugdesignthatreliesontheknowledgeofthethreedimensionalstructureofthe
biomoleculartargetisknownasstructurebaseddrugdesign.
5. 1)LigandBasedDrugDesign 2)StructureBasedDrugdesign
6. Ligandbaseddrugdesign(orindirectdrugdesign)reliesonknowledgeofothermoleculesthatbindto
thebiologicaltargetofinterest. Theseothermoleculesmaybeusedtoderiveapharmacophoremodel
thatdefinestheminimumnecessarystructuralcharacteristicsamoleculemustpossessinordertobindto
thetarget. Inotherwords,amodelofthebiologicaltargetmaybebuiltbasedontheknowledgeofwhat
bindstoit,andthismodelinturnmaybeusedtodesignnewmolecularentitiesthatinteractwiththe
target. Alternatively,aQuantitativeStructureActivityRelationship(QSAR),inwhichacorrelationbetween
calculatedpropertiesofmoleculesandtheirexperimentallydeterminedbiologicalactivity,maybederived.
TheseQSARrelationshipsinturnmaybeusedtopredicttheactivityofnewanalogs.
7. Structurebaseddrugdesign(ordirectdrugdesign)reliesonknowledgeofthethreedimensional
structureofthebiologicaltargetobtainedthroughmethodssuchasxraycrystallographyorNMR
spectroscopy. Ifanexperimentalstructureofatargetisnotavailable,itmaybepossibletocreatea
homologymodelofthetargetbasedontheexperimentalstructureofarelatedprotein. Usingthe
structureofthebiologicaltarget,candidatedrugsthatarepredictedtobindwithhighaffinityandselectivity
tothetargetmaybedesignedusinginteractivegraphicsandtheintuitionofamedicinalchemist.
Alternativelyvariousautomatedcomputationalproceduresmaybeusedtosuggestnewdrugcandidates.
8.Chapter2ComputerAidedDrugDiscovery(Design)
9. Computeraideddrugdesignusescomputationalchemistrytodiscover,enhance,orstudydrugsand
relatedbiologicallyactivemolecules. Themostfundamentalgoalistopredictwhetheragivenmolecule
willbindtoatargetandifsohowstrongly.Molecularmechanicsormoleculardynamicsaremostoften
usedtopredicttheconformationofthesmallmoleculeandtomodelconformationalchangesinthe
biologicaltargetthatmayoccurwhenthesmallmoleculebindstoit. Semiempirical,abinitioquantum
chemistrymethods,ordensityfunctionaltheoryareoftenusedtoprovideoptimizedparametersforthe
molecularmechanicscalculationsandalsoprovideanestimateoftheelectronicproperties(electrostatic
potential,polarizability,etc.)ofthedrugcandidatethatwillinfluencebindingaffinity.
10.????HowDrugsAreDiscovered?
11. Thetraditionalwaytodiscovernewdrugshasbeentoscreenalargenumberofsyntheticchemical
compoundsornaturalproductsfordesirableeffects. Althoughthisapproachforthedevelopmentofnew
pharmaceuticalagentshasbeensuccessfulinthepast,itisnotanidealoneforanumberofreasons
12. Modificationstoimproveperformanceareoftencarriedoutusingchemicalorbiofermentativemeans
tomakechangesintheleadstructureoritsintermediates. Alternatively,forsomenaturalproducts,the
geneitselfmaybeengineeredsothattheproducerorganismsynthesizesthemodifiedcompounddirectly.
13. Asstillmoreinformationbecomesavailableaboutthebiologicalbasisofadisease,itispossibleto
begintodesigndrugsusingamechanisticapproachtothediseaseprocess. Whenthediseaseprocessis
understoodatthemolecularlevelandthetargetmolecule(s)aredefined,drugscanbedesigned
specificallytointeractwiththetargetmoleculeinsuchawayastodisruptthedisease.
14.Chapter3BasicsofMechanismOfDrugDesign
15. DefiningtheDISEASEProcess:Thefirststepinthemechanisticdesignofdrugstotreatdiseasesis
todeterminethebiochemicalbasisofthediseaseprocess.Ideally,onewouldknowthevarioussteps
involvedinthephysiologicalpathwaythatcarriesoutthenormalfunction.Inaddition,onewouldknowthe
exactstep(s)inthepathwaythatarealteredinthediseasedstate.Knowledgeabouttheregulationofthe
pathwayisalsoimportant.Finally,onewouldknowthethreedimensionalstructuresofthemolecules
involvedintheprocess.
16. Therearepotentiallymanywaysinwhichbiochemicalpathwayscouldbecomeabnormalandresult
indisease.Therefore,knowledgeofthemolecularbasisofthediseaseisimportantinordertoselecta
targetatwhichtodisrupttheprocess. Targetformechanisticdrugdesignusuallyfallintothree
categories:enzymes,receptorsandnucleicacids.
17. Enzymesarefrequentlythetargetofchoicefordisruptionofadisease.Ifadiseaseistheresultof
theoverproductionofacertaincompound,thenoneormoreoftheenzymesinvolvedinitssynthesiscan
oftenbeinhibited,resultinginadiseaseinproductionofthecompoundanddisruptionofthedisease
process.
18. Sometimesadiseasecanbemodulatedbyblockingtheactionofaneffectorsatitscellular
receptor. Receptorsthatareeasilyisolatedarethemostamenabletorationaldesignofeffectors.An
illustrativeuseofthisconceptisinthethreedimensionalstructuraldeterminationofrhinoviruses,which
thencanserveasareceptortypetargetforthedesignofantiviraldrugs.
19. Diseasescanalsopotentiallybeblockedbypreventingthesynthesisofundesirableproteinsatthe
nucleicacidlevel. Thisstrategyhasfrequentlybeenemployedintheantimicrobialandantitumorareas,
whereDNAblockingdrugsareusedtopreventthesynthesisofcriticalproteins.
20.Chapter4QUANTITATIVESTRUCTUREACTIVITYRELATIONSHIP(QSAR)
21. QSARmodelsrelatemeasurementsonasetof"predictor"variablestothebehavioroftheresponse
variable. InQSARmodeling,thepredictorsconsistofpropertiesofchemicalstheQSARresponse
variableisthebiologicalactivityofthechemicals. QSARmodelsfirstsummarizeasupposedrelationship
betweenchemicalstructuresandbiologicalactivityinadatasetofchemicals.SecondQSARmodels
predicttheactivitiesofnewchemicals.
22.1)FragmentBased2)3DQSAR3)Modeling
23.Chapter5UsesOfComputerGraphicsinCADD
24. Computersareessentialtoolinmodernmechanicalchemistryandareimportantinbothdrug
discoveryanddevelopment. Thedevelopmentofthispowerfuldesktopenabledthechemisttopredictthe
structureandthevalueofthepropertiesofknown,unknown,stableandunstablemolecularspeciesusing
mathematicalequation.Solvingthisequationgivesrequireddata. Graphicalpackageconvertthedatafor
thestructureofachemicalspeciesintoavarietyofvisualformats.Consequently,inmedicinalchemistry,it
isnowpossibletovisualizethethreedimensionalshapeofboththeligandsandtheirtargetsites.
25.ComputerGraphicDisplaysMolecularModeling Inmolecularmodeling,thedataproducedare
convertedintovisualimageonthecomputerscreenbygraphicpackages. Theseimagesmaybe
displayedinavarietyofstyleslikefill,CPK(CoreyPaulingKoltum),stick,ballandstick,meshandribbon
andcolourschemewithvisualaids.Ribbonpresentationisusedforlargermoleculeslikenucleicacidand
protein.
26. Molecularmechanicsisthemorepopularofthemethodsusedtoobtainmolecularmodelsasitis
simpletouseandrequiresconsiderablylesscomputingtimetoproduceamodel.Inthistechniquethe
energyofstructureiscalculated. Theequationusedinmolecularmechanicsfollowthelawsofclassical
physicsandappliesthemtomolecularnucleiwithoutconsiderationoftheelectrons
27. MolecularmechanicscalculationsaremadeatzeroKelvin,thatisonstructurethatarefrozenintime
andsodonotshowthenaturalmotioninthestructure. Moleculardynamicsprogramsallowthemodular
toshowthedynamicnatureofthemoleculebystimulatingthenaturalmotionoftheatominastructure
28. Usingmolecularmechanics(MM2),itispossibletogenerateavarietyordifferentconformationsby
usingamoleculardynamicsprogramwhichheatsthemoleculeto800900K.Ofcourse,thisdoesnot
meanthattheinsideofyourcomputerisabouttomelt. Itmeansthattheprogramallowsthestructureto
undergobondstretchingandbondrotationasifitwasbeingheated.
29. Unlikemolecularmechanismsthequantummechanicsapproachtomolecularmodelingdoesnot
requiretheuseofparameterssimilartothoseusedinmolecularmechanics. Itisbasedontherealization
thatelectronsandallmaterialparticlesexhibitwavelikeproperties
30.Chapter6ImportantTechniquesofDrugDesign
31. Xraycrystallographyisoftenthestartingpointforgatheringinformationfrommechanisticdrug
design. Thistechnologyhasthepotentialtodeterminetotalstructuralinformationaboutamolecule.
Furthermoreitprovidesthecriticallyimportantcoordinatesneededforthehandlingofdatabycomputer
modelingsyste
32. NMRusesmuchsofterradiationwhichcanexaminemoleculesinthemoremobileliquidphase,so
thethreedimensionalinformationobtainedmaybemorerepresentativeofthemoleculeinitsbiological
environment AnotheradvantageofNMRisitsabilitytoexaminesmallmoleculemacromolecule
complexes,suchasanenzymeinhibitorintheactivesiteoftheenzyme.
33. Useofcomputingpowertostreamlinedrugdiscoveryanddevelopmentprocess Leverageof
chemicalandbiologicalinformationaboutligandsand/ortargetstoidentifyandoptimizenewdrugs
Designofinsilicofilterstoeliminatecompoundswithundesirableproperties(pooractivityand/orpoor
Absorption,Distribution,Metabolism,ExcretionandToxicity,ADMET)andselectthemostpromising
candidates.
34. RoleofcomputeraidedmolecularmodelinginthedesignofnovelinhibitorsofRennin. Inhibitorsof
Dihydrofolatereductase. ApproachestoAntiviraldrugdesign. Conformationbiologicalactivity
relationshipsforreceptorselective,conformationallyconstrainedopioidpeptides. Designof
conformationallyrestrictedcyclopeptidesfortheinhibitionofcholateuptakeofHeepatocytes
35. Theprocessofdrugdiscoveryanddevelopmentisalonganddifficultone,andthecostsof
developingareincreasingrapidly.Todayittakesappropriately10yearsand$100milliontobringanewdrug
 tomarket.
36.Mechanismbaseddrugdesigntacklesmedicalproblemsdirectly.Itprovidesanopportunitytodiscover
entirelynewleadcompoundsnotpossibleusingothertechniquesfordrugdevelopment
37. 1)3rdAnnualBiotechnologyConferenceForStudentsorganizedbyInternationalInstituteof
InformationTechnology(I2IT)Pune,During1213Nov.2011.
38.2)NationalConferenceonFrontiersinBiologicalSciencesorganizedbyVeerBahadurSingh
PurvanchalUniversity,Jaunpur(U.P)during45Dec.2011.3)NationalSeminaronDrugDiscoveryfrom
Plants:PromisesAndChallenges(DDPC2012)OrganizedbySchoolofLifeSciences,S.R.T.M.University,
Nandedduring1415Feb.2012

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