复旦《药物设计学》课件03药物发现的两条主要途径

12DrugDesignology31irrationaldrugdesignHTSHCS•——•——452SBDDMBDDPBDDRationaldrugdesign,Computer-AidedDrugDesign,CADD-SBDDPBDDMBDD6——Nat.Rev.Drug.Discov.16:19-34,20177•20151578FDA893667•166914192508Nat.Rev.DrugDiscov.2011,507-519•1999-2008USFDA259•75first-in-classmolecularmechanismofactionMMOA•50(67%)25(33%)•2817MMOA910:113Structure-baseddrugdesign——12-Langley1878EmilFischer1894P.Ehrich1913KEYLOCK13-()•••141-α-β-β-152-(induced-fit)--induced-fitinduced-fit161()2()21Tyr75173-(KJ/mol)(nm)140-8000.3-1.90.2-0.43.40.2-0.44-300.25-0.3520-400.5-1.0-~20.5-1.0-0.50.2-0.40.5~0.518(vanderWaalsforce,VDW)Hydrophobicregion19hydrogenbond20hydrogenbond21hydrogenbond22ionicbond,ion-ionbond——electrostaticinteraction)-23-dipole-dipoleinteraction——electrostaticinteraction)24induceddipoleinteraction——electrostaticinteraction)-ion-induceddipoleinteraction)-dipole-induceddipoleinteraction)25hydrophobicbondΔG=ΔH-TΔS264-27285(receptophore)(activesite)(bindingsite)——29DHFR-MTXDHFR12-30-31(SAR)pKalogP-32——SARstructure-propertyrelationship,SPR(structure-activityrelationships,SAR)SAR33structure-pharmacokineticsrelationships,SKRstructure-metabolismrelationships,SMRstructure-toxicityrelationships,STRSKRSMRADME——341pharmacophorebiophore35HOOCHCNH2NCH2CH2ClCH2CH2ClNCH2CH2ClCH2CH2ClOHNNHOO36NMeNCH3CH3NHORicasetronClNH2NHONOMeMetoclopramideNNNOCH3CH3Ondansetron5-HT3372(toxicophore)3839ADMEHOOCHCNH2NCH2CH2ClCH2CH2ClNCH2CH2ClCH2CH2ClOHNNHOO3(kinetophore)404(pharmacophoricconformation)AChAChACh*(activeconformation)——40ONOAcetylcholine+41421——2——3——43ligandstructure-baseddrugdesignreceptorstructure-baseddrugdesignstructure-baseddrugdesign44Computer-AidedDrugDesign,CADDComputer-AssistedDrugDesignComputerizedDrugDesigninsilicoDrugDesign451960’s1970’s1980’s1990’s2000’sQSAR/CADDCADD46•••-CADD47CADD48••CADD••49CADDCADD0.91.3CurrentTopicsinMedicinalChemistry,2010,10,127-14150SaquinavirHIV-PR51CADDQSARDDT.Technol.2006,307——)——()——CADD——CADD5253-/-+54••••••••••••••••••••••••55SBDD56JournalofChemicalEducation,74(7):782-783,1997OH(Z)-6-(2,3-diethylcyclopent-2-enyl)-7,7,10,10-tetraethylcyclodec-8-en-2,4-diyn-1-olCowenynenynolOHHO2-(3,3-diethynyl-2,4-divinyl-6,6-diisobutylcycloheptyl)cyclopropanolTurkenynenynol5758(quantumchemistry)1900Planck1913Bohr————————59(SchdingerEquation)61•••GaussianSPARTAN•abinitiomethods62semiempiricalmethods••••MOPACAMPAC63×HOMOLUMO64•••=+65:66bct•EtotalEtotal=Ec+Eb+Et+Ev+Eh+Ee+EdEc(compressionenergy)Eb(bendingenergy)Et(torsionalenergy)EvvandeWaalsenergyEh(hydrogenbondingenergy)Ee(electrostaticenergy)Ed(dipoleenergy)67•——•68ו•10-15697071(energysurface)72••gridsearchtreesearch•(step)73stochasticsearch/randomsearch1.2.74MonteCarloMethodMC——:7576•MonteCarlo•77moleculardynamics,MD——78(simulatedannealingalgorithm)——MonteCarlo79×80monomericretroviralproteaseFoldit3Nat.Struct.Mol.Biol.2011,18(10):1175-1177811998WalterKohnJohnA.Pople822013MartinKarplusMichaelLevittAriehWarshel•Karplus•CHARM•CFF••83X-84(X-raycrystallography)XX••-•X86(NMR)••87•M20000Da88SBDD3D-2D-3D-()3D-(NMR)3D-3D-(NMR)3D-NMR()89computeraidedmolecularmodeling,CAMMcomputerizedmolecularmodeling,CMMmolecularmodelingMM,•——9091——NOHOOHH3C••–––••–•––/•9293NOHOOHH3CCPK94——9596979899100101102————104-105-——106-107•••108(graphicworkstation)••CPUUNIX•SiliconGraphicsIncorporated(SGI),SunGraphics,HP-PA,DECAlphaApolloDell109(supercomputer)••SGI4000A2004113000A20071870002008106.55000A2008230200912062010257020133.3862017110expertsystem111QSAR,,ANN112SGIFUEL•CPU500MHz•1GB•2MB•36GB•21•$31800*50%113TRIPOS•Sybyl/Base•Dynamics•QSARwithCoMFA•AdvancedComputation•Biopolymer•Composer•FlexX3D-QSARSYBYLUnixSYBYLMOEMolecularOperatingEnviroment)(DS)3D-QSARADME——120121(activesiteanalysis)••HOHNOOOH122••GRIDGREENESITEMAPHSITEMCSSHINTBUCKETS123•[]——OOCOOHHOCH3COHNHOOHOHOOHCOOHHOCH3COHNHOOHOHN-N-acetyl-neuraminicacidNeu5AC124Neu5Ac2enR=H2--2,3--D-N-,Neu5Ac2enIC50=1μM,ORCOOHAcNHHOOHOH3D-1251.2.GRID3.:4--Neu5Ac2en;4--Neu5Ac2enORCOOHAcNHHOOHOHR=NH2R=CNH2NHNH1265.:Neu5Ac2en1000nM4--Neu5Ac2en50nM4--Neu5Ac2en0.2nM4.1277.8.Zanamivir1993Glaxo)6.-X-:4--Neu5Ac2en4--Neu5Ac2en128129(denovodrugdesign)130moleculartemplate-directed)(atombuild)(fragmentbuild)(linked-fragmentapproachsitepointconnection):131atombuild1.2.132(fragmentbuild)NOHNNH2HONHNNH2NHHNNH2OOOOOOOOO(a)(b)(c)molecularfragmentapproach133molecularfragmentapproachlinked-fragmentapproach:-OH,C=O,-X:-CH2-,-CH2CH2-,-CH2CH2CH2-,-CH=CH-,-COO-,CONH-,-O-NOHNNH2HOOOONHNNH2HOOOOONHHNNH2HOOOO(a)(b)(c)134•••,135[]DHFR——(dihydroflatereductase,DHFR)DHFR——,DHFR2.LEGENDLORE3009NHCH3H3COHO1.DHFR-----PDBDHFR-II--DHFR-II1363.:1373D-QSAR——1383D-QSARHASLMSACoMFAAAA139Pharmacophoremodeling3D-QSAR140••pharmacophoricelements——()••141Pharmacophoreperception1421(target-basedpharmacophore)--143••Sybyl/ReceptorDisco/DiscoTechAccelrys/Catalyst1442(ligand-basedpharmacophore)()145146147——N2NCH3CH3OHOCH3OONOCH3HH3COHHH++2Cl-.148ActiveAnalogueApproach,AAA149[]AAA150151N