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Oct.8th,2018李炜基于靶点的药物设计TargetBasedDrugDesign药物设计学引言:一个药物的发现历程2Anexample:乙酰水杨酸的发现phenol(1842)salicylicacid(1860)aspirin(1896)防腐消毒抗炎杀菌salicin解热镇痛抗炎Kolbe-Schmitt反应乙酰水杨酸的作用机制31971年阿司匹林的作用机制阐明:不可逆抑制cyclooxygenase(COX)细胞损伤磷脂酶A2COXPGE2PGF2αPGD2PGH2NSAIDsPGE合成酶PGF合成酶PGD合成酶ArachidonicAcid花生四烯酸X-raycrystalstructureofAspirin-COX-1complex通过作用于环氧合酶发挥解热、镇痛、抗炎作用非甾体类抗炎药解热镇痛药非甾体类抗炎药(狭义)水杨酸类吡唑酮类3,5-吡唑烷二酮类芬那酸类芳基烷酸类1,2-苯并噻嗪类选择性COX2抑制剂芳基乙酸类芳基丙酸类阿司匹林乙酰水杨酸安乃近保泰松双氯芬酸吲哚美辛布洛芬吡罗昔康塞来昔布苯胺类?ADrugDiscoveryParadigm6药物机制疾病机制药物疾病PhenotypeClassicalModernTranslationActivityScreeningObservationHypothesisTheConceptofDrugTarget7PaulEhrlich(1854-1915)Strebhardt,K,etal.NatRevCancer,2008Jun;8(6):473-80.药物设计基本原理靶点理论(TheoryofDrugTarget)8•与靶点发生相互作用(药效学要求);•暴露于靶点,药物到达靶点、达到适宜的浓度Cmax且/或维持足够长的时间AUC(药代动力学要求);•减少因中靶(on-target)及脱靶(off-target)所引起的副作用靶点的识别——正向识别CauseversusEffectProblem靶点的识别——逆向识别Translationconcerns靶点的识别:ClinicalTrials11ClassificationofDrugTargets12细胞膜受体,45%酶,28%细胞因子/激素,11%离子通道,5%核酸,2%核受体,2%其他,7%受体(Receptors)类型药物活性举例Directligand-gatedionchannelreceptorsGABAAreceptorsBarbituratebindingsiteagonistsBarbiturateBenzodiazepinebindingsiteagonistsBenzodiazepinesAcetylcholinereceptorsNicotinicreceptoragonistslevamisoleNicotinicreceptordepolarizingantagonistsSuxamethoniumNicotinicreceptorallostericmodulatorsGalantamineGlutamatereceptors(ionotropic)NMDAsubtypeantagonistsMemantineNMDAsubtypephencyclidinebindingsiteantagonistsKetamineNatureReviewsDrugDiscovery,2006,vol5,821受体(Receptors)类型药物活性举例G-protein-coupledreceptorsAcetylcholinereceptorsMuscarinicreceptoragonistsPilocarpineMuscarinicreceptorantagonistsTropanederivativesAdenosinereceptorsAdenosineA1receptorantagonistsCaffeineTheophyllineAdrenoceptorsAgonistsnoradrenaline,ephedrineα1-receptorantagonistsErgotamineα2-receptor,centralagonistsMethyldopaβ1-receptorantagonistsPropranolol,atenololβ2-receptoragonistsSalbutamolAngiotensinreceptorsAT1-receptorsantagonistsSartansNatureReviewsDrugDiscovery,2008,vol5,821类型药物活性举例G-protein-coupledreceptorsCysteinyl-leukotrienereceptorsAntagonistsMontelukastDopaminereceptorsDopaminereceptorsubtypedirectagonistsRopinirolepramipexoleD2,D3andD4antagonistsChlorpromazine,fluphenazine,haloperidolGABABreceptorsAgonistsBaclofenHistaminereceptorsH1-antagonistsDiphenhydramineH2-antagonistsCimetidineOpioidreceptorsμ-opioidagonistsMorphine,fentanylopioidantagonistsNaloxoneκ-opioidantagonistsBuprenorphineNatureReviewsDrugDiscovery,2006,vol5,821受体(Receptors)类型药物活性举例G-protein-coupledreceptorsProstanoidreceptorsAgonistsMisoprostolPurinergicReceptorsP2Y12antagonistsClopidogrelSerotoninreceptors5-HT1ApartialagonistsBuspirone5-HT1B/1DagonistsSumatriptan5-HT2AantagonistsQuetiapine,Ziprasidone5-HT3antagonistsGranisetronIntegrinreceptorsGlycoproteinIIb/IIIareceptorAntagonistsTirofibanReceptorsassociatedwithatyrosinekinaseInsulinreceptorDirectagonistsInsulinSensitizersBiguanidesNatureReviewsDrugDiscovery,2006,vol5,821受体(Receptors)类型药物活性举例Nuclearreceptors(steroidhormonereceptorsandothers)MineralocorticoidreceptorAgonistsAldosteroneAntagonistsSpironolactoneGlucocorticoidreceptorAgonistsGlucocorticoidsOestrogenreceptorAgonistsOestrogens(Partial)agonistsClomifeneAntagonistsFulvestrantModulatorsTamoxifenPeroxisomeproliferatoractivatedreceptor(PPAR)PPARαagonistsFibratesPPARγagonistsGlitazonesThyroidhormonereceptorsAgonistsL-ThyroxineNatureReviewsDrugDiscovery,2006,vol5,821受体(Receptors)靶酶(Enzymes)类型药物活性举例Hydrolases(proteases)Aspartylproteases(viral)HIVproteaseinhibitorSaquinavir,indinavirHydrolases(serineproteases)BacterialserineproteaseDirectinhibitorβ-lactamsBacteriallactamasesDirectinhibitorSulbactamHumanantithrombinActivatorHeparinsHumanplasminogenActivatorStreptokinaseHydrolases(metalloproteases)HumanACEInhibitorCaptoprilHumanHRD(dehydropeptidase)InhibitorCilastatinHydrolases(other)26SproteasomeInhibitorBortezomib类型药物活性举例Hydrolases(other)Glycosidases(viral)α-glycosidaseinhibitorZanamivir,oseltamivirGlycosidases(human)α-glycosidaseinhibitorAcarboseEsterasesAChEinhibitorPhysostigminePDE3inhibitorAmrinon,milrinonePDE5inhibitorSildenafilDOPAdecarboxylaseInhibitorCarbidopaCarbonicanhydraseInhibitorAcetazolamideIsomerasesDNAgyrases(bacterial)InhibitorFluoroquinolonesNatureReviewsDrugDiscovery,2006,vol5,821靶酶(Enzymes)类型药物活性举例IsomerasesTopoisomerasesTopoisomeraseIinhibitorCamptothecin,IrinotecanTopoisomeraseIIinhibitorEtoposideΔ8,7isomerase(fungal)InhibitorAmorolfinLigases(alsoknownassynthases)DihydropteroatesynthaseInhibitorSulphonamidesThymidylatesynthase(fungalandhuman)InhibitorFluorouracilOxidoreductasesMonoamineoxidases(MAOs)MAO-AinhibitorMoclobemideMAO-BinhibitorSelegilineCyclooxygenases(COXs)InhibitorNSAIDsNatureReviewsDrugDiscovery,2006,vol5,821靶酶(Enzymes)类型药物活性举例OxidoreductasesVitaminKepoxidereductaseInhibitorWarfarin,phenprocoumonAromataseInhibitorletrozoleLanosteroldemethylase(fungal)InhibitorAzoleantifungalsLipoxygenases5-lipoxygenaseinhibitorZileutonHMG-CoAreductaseInhibitorStatinsDihydrofolatereductase(bacterial,human,parasitic)InhibitorTrimethoprim,pyrimethamine,MethotrexateDihydroorotate
本文标题:复旦《药物设计学》课件02基于靶点的药物设计
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