Label-Free Technologies For Drug Discovery

335 Pages·2011·21.55 MB·English

by  Matthew Cooper

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Label-Free Technologies
For Drug Discovery
Label-Free Technologies for Drug Discovery Edited by Matthew Cooper and Lorenz M. Mayr
© 2011 John Wiley & Sons, Ltd. ISBN: 978-0-470-74683-7
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Label-Free Technologies
For Drug Discovery
Editors
Matthew Cooper
Institute for Molecular Bioscience,
University of Queensland, Australia
Lorenz M. Mayr
Biology Unit, Protease Platform, Novartis Pharma AG,
Basel, Switzerland
A John Wiley and Sons, Ltd., Publication
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Thiseditionfirstpublished2011
(cid:1)C 2011JohnWiley&Sons,Ltd
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LibraryofCongressCataloging-in-PublicationData
Label-freetechnologiesfordrugdiscovery/editors,MatthewCooper,LorenzM.Mayr.
p.;cm.
Includesbibliographicalreferencesandindex.
ISBN978-0-470-74683-7(cloth)
1.Drugdevelopment. I.Cooper,M.A.(MatthewA.) II.Mayr,M.Lorenz.
[DNLM:1.DrugDiscovery. 2.BiosensingTechniques. 3.DrugDesign.QV744]
RM301.25.L33 2011
615(cid:2).19–dc22
2010042191
AcataloguerecordforthisbookisavailablefromtheBritishLibrary.
PrintISBN:9780470746837
ePDFISBN:9780470979136
oBookISBN:9780470979129
ePubISBN:9781119990277
Typesetin10.5/13ptSabonbyAptaraInc.,NewDelhi,India.
PrintedinSingaporebyMarkonoPrintMediaPteLtd
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Contents
Preface xv
ListofContributors xix
1 TheRevolutionofReal-Time,Label-FreeBiosensor
Applications 1
RebeccaL.RichandDavidG.Myszka
1.1 Introduction 1
1.2 SPRPessimists 4
1.3 SettingUpExperiments 8
1.4 DataProcessingandAnalysis 13
1.5 TheGoodNews 22
References 25
2 DesignandImplementationofVerticallyEmitting
DistributedFeedbackLasersforBiologicalSensing 27
MengLu,StevenS.Choi,ChunGe,ClarkJ.Wagner,J.
GaryEden,andBrianT.Cunningham
2.1 Introduction 28
2.2 DFBLaserBiosensorDesign 29
2.3 FabricationandInstrumentation 32
2.4 ExperimentalResults 34
2.4.1 VerticallyEmittingDFBLaser 34
2.4.2 BulkMaterialSensing 34
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vi CONTENTS
2.4.3 SensitivityResolution 36
2.4.4 SmallMoleculeBindingDetection 38
2.5 Conclusions 39
Acknowledgements 39
References 40
3 SPRScreeningofChemicalMicroarraysfor
Fragment-BasedDiscovery 41
ThomasNeumannandRenateSekul
3.1 Introduction 42
3.2 KeyFeaturesofFragmentScreening 42
3.3 SPRFragmentScreening 42
3.4 SynthesisofLibraryCompounds 43
3.5 LibraryDesignandArrayContent 44
3.6 ChemicalMicroarrayProduction 46
3.7 SurfacePlasmonResonance 48
3.8 SPRImaging 49
3.9 ArrayVisualizationandAnalysis 50
3.10 Follow-up 52
3.11 Applications:MMPCaseStudy 52
3.11.1 SearchforNewBindingModes 52
3.11.2 SelectivityStudies 53
3.12 OtherTargetClasses 54
3.13 Conclusion 54
References 55
(cid:1)
4 TheCellKeyR System:ALabel-FreeCell-BasedAssay
PlatformforEarlyDrugDiscoveryApplications 57
RyanP.McGuinness,DebraL.Gallant,Yen-WenChen,
TrishaA.Tutana,DonnaL.Wilson,JohnM.Proctor,
andH.RogerTang
4.1 Introduction 57
4.2 CellularImpedanceTechnology 59
4.3 TargetIdentificationandValidation 62
4.4 ScreeningandLeadOptimization 65
4.5 Conclusion 68
References 69
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CONTENTS vii
5 DynamicandLabel-FreeCell-BasedAssaysUsingthe
xCELLigenceSystem 71
YamaA.Abassi,AlexanderSieler,ManfredWatzele,
XiaoboWang,andXiaoXu
5.1 Introduction 72
5.2 ThexCELLigenceSystem 73
5.3 PrincipleofDetection 74
5.4 Applications 74
5.4.1 CellProliferation,CytotoxicityandTime
DependentCellularResponseProfiling 74
5.5 FunctionalAssaysforG-ProteinCoupledReceptors 78
5.6 Conclusion 80
References 80
6 SelectingtheBestHTSHitstoMoveForward:ITCLigand
BindingCharacterizationProvidesGuidance 83
RonanO’BrienandRichardBrown
6.1 Introduction 84
6.2 PrinciplesofIsothermalTitrationCalorimetry
(ITC) 85
6.3 ApplicationsofITCinHitValidation 85
6.3.1 AssayDesignforHitConfirmationand
AffinityDetermination 86
6.3.2 IdentificationofNonspecificBinders,
UnstableProteinTargetsandMultiple
BindingSites 88
6.3.3 HighSpeedITCHitCharacterizationAssays 88
6.4 ApplicationsofITCinFragment-BasedDrug
Discovery 90
6.4.1 MeasuringWeakAffinitiesbyITC 90
6.5 ApplicationsofITCinMechanismofAction
Studies 93
6.6 ApplicationsofITCinLeadOptimization 94
6.7 ITCasanEnzymeActivityMonitor 97
6.8 Conclusion 98
References 99
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viii CONTENTS
7 IncorporatingTransmittedLightModalitiesinto
High-ContentAnalysisAssays 101
RobertGraves
7.1 Introduction 101
7.2 TransmittedLight(BrightField)Imaging 103
7.3 ImageAnalysisofPhaseContrastImages 103
7.4 Conclusion 108
References 110
8 NonradioactiveRubidiumEffluxAssayTechnologyfor
ScreeningofIonChannels 111
GeorgC.Terstappen
8.1 Introduction 111
8.2 IonChannelsasDrugTargets 113
8.3 IonChannelAssaysandScreening 114
8.4 NonradioactiveRubidiumEffluxAssayBasedon
AtomicAbsorptionSpectrometry 114
8.5 ATypicalAssayProtocol 119
8.6 Conclusions 121
References 122
9 ExpandingtheScopeofHTMSMethods 125
TomG.Holt,JunWang,XunChen,BernardK.Choi,
NeilS.Geoghagen,KristianK.Jensen,MaxineJonas,
QiLuo,WilliamA.LaMarr,LorraineMalkowitz,
CanC.Ozbal,YushengXiong,ClaudeDufresne,and
Ming-JuanLuo
9.1 Introduction 126
9.2 DevelopmentoftheHTMSMethodfor
UnderivatizedCystathionineinBiologicalSamples
SpanningInVivoCellCulture,andExVivoAssays 127
9.2.1 AnalyticalMethodDevelopment 127
9.2.2 AssayDevelopment 130
9.3 Developmentofa2DHTMSMethodfor
Plasma-boundSmallMolecules 133
9.3.1 AnalyticalMethodDevelopment 133
9.3.2 ApplicationtoSmallPeptideinPlasma 134
9.4 Conclusion 137
References 139
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CONTENTS ix
10 ANovelMultiplexSPRArrayforRapidScreeningand
AffinityDeterminationofMonoclonalAntibodies:The
ProteOnXPR36LabelFreeSystem:KineticScreeningof
MonoclonalAntibodies 141
VeredBronner,OdedNahshol,andTsafrirBravman
10.1 Introduction 142
10.2 OptimizedAssayConfiguration 143
10.3 SelectionoftheOptimalCaptureAgent 143
10.4 KineticAnalysisof192HumanAnti-IL-12
Supernatants 147
10.5 KineticAnalysisof243HumanHemoglobin
Supernatants 151
10.6 Conclusions 153
References 154
11 Biophysics/Label-FreeAssaysinHitDiscoveryand
Verification 155
JohannesOttl
11.1 Introduction 156
11.2 WhyBiophysics? 156
11.2.1 QuestsofLeadDiscoveryProgram
TeamsforBiophysics 158
11.3 Biophysics/Label-FreeToolbox 158
11.4 WhichBiophysicalMeasurementatWhichStage
ofaDrugDiscoveryProjectFlowchart? 159
11.4.1 HitFinding 159
11.4.2 HitValidation 160
11.4.3 HitExpansion 161
11.5 ExamplesofHigherThroughputBiophysics
AppliedinHitandLeadFinding 162
11.5.1 CompoundAggregationArtifacts 162
11.5.2 DirectBindingofCompoundson
Proteins:HighThroughputisStill
Challenging! 163
11.5.3 AffinityMSScreening:Qualitativeand
QuantitativeScreeningFreeinSolution 165
11.6 Conclusion 167
11.7 Outlook 168
References 169
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x CONTENTS
12 HarnessingOpticalLabel-FreeonMicrotiterPlatesfor
LeadFinding:FromBindingtoPhenotypes 171
JulioMartin
12.1 Introduction 172
12.1.1 What’sLimitingtheDevelopmentof
Chemical-Genomics? 172
12.1.2 WhyareBiologicalAssaysofthe
TherapeuticRelevanceofa
CompoundNotEquallyPredictable? 174
12.1.3 CompoundsHittinganAssayarenot
AlwaysGenuineandTractableHitsof
theTarget 174
12.2 ValuePropositionandAdvantagesofLabel-Free
Methodologies 175
12.3 DetectionPrincipleofanOpticalLabel-Free
ResonantGratingSensor 177
12.4 BiologicalApplicationsofOpticalLabel-Freein
LeadDiscovery 179
12.4.1 DirectBindingofCompoundLibraries
toProteinTargets 180
12.4.2 FunctionalBiochemicalAssays 182
12.4.3 CellularPhenotypicAssays 182
12.5 CurrentandFutureChallenges 185
12.6 Conclusion 186
References 187
13 UseofLabel-FreeDetectionTechnologiesinthe
Hit-to-LeadProcess:SurfaceOpticalDetectionofCellular
Processes 189
F.Stuhmeier,J.Bradley,E.Fairman,E.Gbekor,
P.Hayter,andS.Ramsey
13.1 Introduction 190
13.2 OverviewofLabel-FreeAssayPlatforms 191
13.3 SurfaceOpticalDetectionofCellularProcesses 193
13.3.1 ExperimentalDetails 193
13.3.2 ResultsfromRecombinantCellularAssays 195
13.4 Discussion 200
References 203
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CONTENTS xi
14 CellularScreeningfor7TMReceptorsUsingLabel-Free
Detection 205
JeffreyC.Jerman,JasonBrown,andMagalieRocheville
14.1 Introduction 206
14.2 ResultsandDiscussion 207
14.2.1 CompoundProfiling 207
14.2.2 HitIdentification 213
14.3 ConclusionsandPerspective 217
14.4 MaterialsandMethods 218
14.4.1 Materials 218
14.4.2 Methods 219
14.4.3 DataAnalysisandStatistics 221
Acknowledgements 221
References 221
15 NovartisEvaluationoftheForteBioOctetRED:A
VersatileInstrumentforDirectBindingExperiments 223
EricMartin,JohnWang,IsabelZaror,JiaminYu,
KellyYan,MikeDoyle,PaulFeucht,KevinShoemaker,
BobWarne,MikeChin,BlissethSy,LukasLeder,
MarcoMeyerhofer,CharlesWartchow,and
DanfengYao
15.1 Introduction 224
15.2 Methods 226
15.2.1 ProductionofProteins 226
15.2.2 ProteinLoadingandSmallMolecule
BindingAnalysis 226
15.2.3 Referencing 228
15.2.4 DataAnalysis 229
15.2.5 BindingStudies 229
15.3 ResultsandDiscussion 231
15.3.1 Protein“E” 231
15.3.2 Protein“D” 232
15.3.3 Protein“K” 234
15.3.4 MediumThroughputScreening 235
15.3.5 Protein“P” 236
15.4 Conclusion 239
References 240