2007Protein Crystallography in Drug Discovery

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1、3.38ProteinCrystallographyinDrugDiscoveryTHoggandRHilgenfeld,UniversityofLu¨beck,Lu¨beck,Germany&2007PublishedbyElsevierLtd.3.38.1Introduction:TheCostandValueofMacromolecularCrystallographyinDrugDiscovery8753.38.2MacromolecularCrystallographyandRationalDrugDesign:AHistoricalPerspec

2、tive8763.38.3CrystallographicMilestonesinRationalDrugDesign8773.38.3.1Milestone1:GenetoProtein8773.38.3.1.1Domainmappingandrationaldeoxyribonucleicacidconstructdesign8793.38.3.1.2Affinitychromatography:findingtherighttag8803.38.3.1.3Choosingasuitableexpressionsystem8803.38.3.2Milesto

3、ne2:FromProteintoCrystal8803.38.3.2.1Solubilityoptimization:thefirsthurdlebetweenpurificationandcrystallization8813.38.3.2.2Proteincharacterization:fitforcrystallization?8813.38.3.2.3Dealingwithheterogeneity8813.38.3.2.4Theproteinasavariable8843.38.3.3Milestone3:FromCrystaltoStructure

4、8883.38.3.3.1Postcrystallizationtreatmentstoimprovediffractionquality8883.38.3.3.2Cryocrystallographyinpractice8893.38.3.3.3Phasingmethodsfordrugdiscovery8893.38.3.4Milestone4:StructuretoLead8903.38.3.4.1Crystallography-drivenleadcharacterization:thetraditionalview8903.38.3.4.2Crys

5、tallographyandfragonomics:theemergingareaoffragment-baseddrugdesign8923.38.4TheEraofHigh-ThroughputCrystallographyinLeadDiscovery894References8943.38.1Introduction:TheCostandValueofMacromolecularCrystallographyinDrugDiscoveryDrugdiscoveryhastraditionallyreliedeitheronserendipitouso

6、bservations(aclassicexamplewouldbeSirAlexander1Flemingsdiscoveryoftheantibacterialpropertiesofpenicillin),oronscreeningofnaturalandsyntheticcompoundsincombinationwithmedicinalchemistry(see1.07OverviewofSourcesofNewDrugs;3.32High-ThroughputandHigh-ContentScreening).Whileremainingind

7、ispensabletothedrugdiscoveryprocess,theconventionalmethodsarebeginningtogivewaytomorerationalapproachesthatutilizeavailableknowledgeonthethree-dimensional(3D)2structureofadrugtarget(see4.24Structure-BasedDrugDesignTheUseofProteinStructureinDrugDiscovery).Thisinformationcanbegenerat

8、edexperimentallybyemployin