Drug discovery and development-药物发现与发展.ppt

DrugDiscovery Development Introduction Inthepastmostdrugshavebeendiscoveredeitherbyidentifyingtheactiveingredientfromtraditionalremediesorbyserendipitousdiscovery Butnowweknowdiseasesarecontrolledatmolecularandphysiologicallevel Alsoshapeofanmoleculeatatomicleveliswellunderstood InformationofHumanGenome HistoryofDrugDiscovery Registration TheMinistryofhealth FamilyWelfareandtheMinistryofChemicals FertilizershavemajorroleinregulationofIPM NDAmustbesubmittedtoDCGIPhaseIIIstudyreportedtoCDL KolkataPackageinsertedapprovedbyDCIMarketingapprovalfromFDA 800Mspenttobringanewdrugtomarket 127BillionspentonPharmaR Din2010ShareofCROsinresearchoperationsis27 WorldCROmarketis16 3B Indianshare 500M MarketScenerio TopCROs ByRevenue TopCROs India MostvaluableR DProjects TopCompaniesbyR DExpense DrugDevelopmentCostBreak up 10 000COMPOUNDS 250COMPOUNDS 5COMPOUNDS 1FDAAPPROVEDDRUG 6 5YEARS 7YEARS 1 5YEARS DRUGDISCOVERY PRECLINICAL CLINICALTRIALS FDAREVIEW DrugDiscovery Development Timeline DrugDiscovery DrugsDiscoverymethods RandomScreeningMolecularManipulationMolecularDesigningDrugMetabolitesSerendipity TargetSelection Targetselectionindrugdiscoveryisdefinedasthedecisiontofocusonfindinganagentwithaparticularbiologicalactionthatisanticipatedtohavetherapeuticutility isinfluencedbyacomplexbalanceofscientific medicalandstrategicconsiderations Targetidentification toidentifymoleculartargetsthatareinvolvedindiseaseprogression Targetvalidation toprovethatmanipulatingthemoleculartargetcanprovidetherapeuticbenefitforpatients TargetSelection BiochemicalClassesofDrugTargetsG proteincoupledreceptors 45 enzymes 28 hormonesandfactors 11 ionchannels 5 nuclearreceptors 2 TechniquesforTargetIdentification Cellular GeneticTargets Involvestheidentificationofthefunctionofapotentialtherapeuticdrugtargetanditsroleinthediseaseprocess Forsmall moleculedrugs thisstepintheprocessinvolvesidentificationofthetargetreceptorsorenzymeswhereasforsomebiologicapproachesthefocusisatthegeneortranscriptionlevel Drugsusuallyactoneithercellularorgeneticchemicalsinthebody knownastargets whicharebelievedtobeassociatedwithdisease Cellular GeneticTargets Scientistsuseavarietyoftechniquestoidentifyandisolateindividualtargetstolearnmoreabouttheirfunctionsandhowtheyinfluencedisease Compoundsarethenidentifiedthathavevariousinteractionswiththedrugtargetsthatmightbehelpfulintreatmentofaspecificdisease Genomics Thestudyofgenesandtheirfunction Genomicsaimstounderstandthestructureofthegenome includingthemappinggenesandsequencingtheDNA Seekstoexploitthefindingsfromthesequencingofthehumanandothergenomestofindnewdrugtargets HumanGenomeconsistsofasequenceofaround3billionnucleotides theACGTbases whichinturnprobablyencode35 000 50 000genes Genomics Drew sestimatesthatthenumberofgenesimplicatedindisease boththoseduetodefectsinsinglegenesandthosearisingfromcombinationsofgenes isabout1 000Basedon5or10linkedproteinspergene heproposesthatthenumberofpotentialdrugtargetsmayliebetween5 000and10 000 SingleNucleotidePolymorphism SNP libraries areusedtocomparethegenomesfrombothhealthyandsickpeopleandtoidentifywheretheirgenomesvary Proteomics Itisthestudyoftheproteome thecompletesetofproteinsproducedbyaspecies usingthetechnologiesoflarge scaleproteinseparationandidentification Itisbecomingincreasinglyevidentthatthecomplexityofbiologicalsystemsliesattheleveloftheproteins andthatgenomicsalonewillnotsufficetounderstandthesesystems Itisalsoattheproteinlevelthatdiseaseprocessesbecomemanifest andatwhichmost 91 drugsact Therefore theanalysisofproteins includingprotein protein protein nucleicacid andproteinligandinteractions willbeutmostimportancetotargetdiscovery Proteomics Proteomicsisthesystematichigh throughputseparationandcharacterizationofproteinswithinbiologicalsystems Targetidentificationwithproteomicsisperformedbycomparingtheproteinexpressionlevelsinnormalanddiseasedtissues 2DPAGEisusedtoseparatetheproteins whicharesubsequentlyidentifiedandfullycharacterizedwithLC MS MS Bioinformatics Bioinformaticsisabranchofmolecularbiologythatinvolvesextensiveanalysisofbiologicaldatausingcomputers forthepurposeofenhancingbiologicalresearch Itplaysakeyroleinvariousstagesofthedrugdiscoveryprocessincludingtargetidentificationcomputerscreeningofchemicalcompoundsandpharmacogenomics Bioinformatics Bioinformaticsmethodsareusedtotransformtherawsequenceintomeaningfulinformation eg genesandtheirencodedproteins andtocomparewholegenomes diseasevs not Cancomparetheentiregenomeofpathogenicandnon pathogenicstrainsofamicrobeandidentifygenes proteinsassociatedwithpathogenismUsinggeneexpressionmicroarraysandgenechiptechnologies asingledevicecanbeusedtoevaluateandcomparetheexpressionofupto20000genesofhealthyanddiseasedindividualsatonce LeadDiscovery IdentificationofsmallmoleculemodulatorsofproteinfunctionTheprocessoftransformingtheseintohigh contentleadseries SynthesisandIsolation SeparationofmixtureSeparationofimpuritiesInvitrochemicalsynthesisBiosyntheticintermediate CombinatorialChemistry Rapidsynthesisoforcomputersimulationoflargeno ofdifferentbutstructurallyrelatedmoleculesSearchnewleadsOptimizationoftargetaffinity selectivity ADMEpropertiesReducetoxicityandeliminatesideeffects AssayDevelopment Usedformeasuringtheactivityofadrug Discriminatebetweencompounds Evaluate Expressedproteintargets Enzyme substrateinteractions Highthroughputscreening Screeningofdrugtargetagainstselectionofchemicals Identificationofhighlytargetspecificcompounds Highthroughputscreening MedicinalChemistry It sadisciplineattheintersectionofsyntheticorganicchemistryandparmacology Focusesonsmallorganicmolecules andnotonbiologicsandinorganiccompounds UsedinDrugdiscovery hits Leadoptimization hittolead Processchemistryanddevelopment LibraryDevelopment Collectionofstoredchemicalsalongwithassociateddatabase AssistsinHighThroughputScreeningHelpsinscreeningofdrugtarget hit Basedonorganicchemistry SARStudies HelpsidentifypharmacophoreThepharmacophoreistheprecisesectionofthemoleculethatisresponsibleforbiologicalactivityEnablestopreparemoreactivecompoundAlloweliminationofexcessivefunctionality SARStudies MorphineMolecule Insilicoscreening ComputersimulatedscreeningofchemicalsHelpsinfindingstructuresthataremostlikelytobindtodrugtarget FilterenormousChemicalspaceEconomicthanHTS ChemicalSynthesis Involveproductionofleadcompoundinsuitablequantityandqualitytoallowlargescaleanimalandeventual extensivehumanclinicaltrialsOptimizationofchemicalrouteforbulkindustrialproduction Suitabledrugformulation InVitroStudies Inglass studiesusingcomponentoforganismi e testtubeexperimentsExamples CellsderivedfrommulticellularorganismsSubcellularcomponents Ribosomes mitochondria Cellular subcellularextracts wheatgerm reticulocyteextract Purifiedmolecules DNA RNA InVitroStudies Advantages Studiescanbecompletedinshortperiodoftime Reducesriskinpostclinicaltrialspermitsanenormouslevelofsimplificationofthesysteminvestigatorcanfocusonasmallnumberofcomponents Drugaffinityandselectivity Drugaffinityistheabilityofdrugtobindtoitsbiologicaltarget receptor enzyme transportsystem etc Selectivity Drugshouldbindtospecificreceptorsiteonthecell eg Aspirin Isogenichumandiseasemodels areafamilyofcellsthatareselectedorengineeredtoaccuratelymodelthegeneticsofaspecificpatientpopulation invitroStemcelldiseasemodels Adultorembryonicstemcellscarryingorinducedtocarrydefectivegenescanbeinvestigatedinvitrotounderstandlatentmolecularmechanismsanddiseasecharacteristics Celldiseasemodels OptimizingchemicalhitsforclinicaltrialiscommonlyreferredtoasleadoptimizationTherefinementinstructureisnecessaryinordertoimprovePotencyOralAvailabilitySelectivitypharmacokineticpropertiessafety ADMEproperties LeadCandidaterefinement Invivostudies Itsexperimentationusingawhole livingorganism Givesinformationabout MetabolicprofileToxicologyDruginteraction Animalmodelsofdiseasestates Testconditionsinvolvinginduceddiseaseorinjurysimilartohumanconditions Mustbeequivalentinmechanismofcause Canpredicthumantoxicityin71 ofthecases Eg SCIDmice HIVNODmice DiabetesDaniorerio Genefunction BehaviouralStudies Toolstoinvestigatebehaviouralresultsofdrugs Usedtoobservedepressionandmentaldisorders Howeverselfesteemandsuicidalityarehardtoinduce Example Despairbased Forcedswimming TailsuspensionRewardbasedAnxietyBased FunctionalImaging Methodofdetectingormeasuringchangesinmetabolism bloodflow regionalchemicalcomposition andabsorption Tracersorprobesused ModalitiesUsed MRICT Scan Ex VivoStudies Experimentationontissueinanartificialenvironmentoutsidetheorganismwiththeminimumalterationofnaturalconditions Countersethicalissues Examples MeasurementoftissuepropertiesRealisticmodelsforsurgery Clinicaltrials Setofproceduresinmedicalresearchanddrugdevelopmenttostudythesafetyandefficacyofnewdrug Essentialtogetmarketingapprovalfromregulatoryauthorities Mayrequireupto7years Phase0 Recentdesignation alsoknownashumanmicro dosingstudies Firstinhumantrials conductedtostudyexploratoryinvestigationalnewdrug Designedtotospeedupthedevelopmentofpromisingdrugs Concernedwith Preliminarydataonthedrug spharmacodynamicsandpharmacokineticsEfficacyofpre clinicalstudies PhaseI ClinicalPharmacologicEvaluationFirststageoftestinginhumansubjects 20 50HealthyVolunteersConcernedWith HumanToxicity ToleratedDosageRangePharma cology dynamics PhaseI TypesofPhase ITrialsSAD SingleAscendingDose MAD MultipleAscendingDose Foodeffect PhaseII ControlledClinicalEvaluation 50 300PatientsControlledSingleBlindTechniqueConcernedWith SafetyEfficacyDrugToxicityDrugInteraction PhaseIII ExtendedClinicalTrials Mostexpensive timeconsuming 250 1000Patients ControlledDoubleBlindTechnique ConcernedWith Safety EfficacyComparisonwithotherDrugsPackageInsert PhaseIV PostMarketingSurveillance Designedtodetectanyrareorlong termadverseeffects AdverseDrugReactionMonitoring Pharmacovigilance 10 000COMPOUNDS 250COMPOUNDS 5COMPOUNDS 1FDAAPPROVEDDRUG 6 5YEARS 7YEARS 1 5YEARS DRUGDISCOVERY PRECLINICAL CLINICALTRIALS FDAREVIEW DrugDiscovery Development Timeline GeneTherapy Techniqueforcorrectingdefectivegenes Itistheprocessofinsertinggenesintocellstotreatdiseases Genetherapyisusedtocorrectadeficientphenotype GeneTherapy Approaches GermlineGeneTherapySpermoreggs aremodifiedbytheintroductionoffunctionalgenes whichareintegratedintotheirgenomes Changewouldbeheritableandwouldbepassedontolatergenerations SomaticGeneTherapyThetherapeuticgenesaretransferredIntothesomaticcellsofapatient Changewillnotbeinheritedbythepatient soffspringorlatergenerations GeneTherapy Types ExVivoGeneTherapyTransferoftherapeuticgenesinculturedcellswhicharethenreintroducedintopatient Eg TherapyforADADeficiencyInVivoGeneTherapyThedirectdeliveryofgenesintothecellsofaparticulartissueisreferredtoasinvivogenetherapy Eg TherapyforCysticfibrosis GeneTherapy Vect