Protein-Protein Interactions in Drug Discovery

329 Pages·2013·17.105 MB·English

by  R. Mannhold, H. Kubinyi, G. Folkers(eds.)

Editedby
AlexanderD€omling
Protein–ProteinInteractions
inDrugDiscovery
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MethodsandPrinciplesinMedicinalChemistry
EditedbyR.Mannhold,H.Kubinyi,G.Folkers
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Protein Protein Interactions
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Cut-awayviewoftheco-crystalstructureofan
archetypicalprotein-proteininteraction:the CoverDesign SchulzGrafik-Design,Fu(cid:2)g€onheim
tumorsuppressorp53andtheoncogene
PrintISBN: 978-3-527-33107-9
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j
V
Contents
ListofContributors XI
Preface XV
APersonalForeword XVII
1 Protein–ProteinInteractions:AnOverview 1
ChristianOttman
1.1 Introduction 1
1.2 RoleofPPIsinHumanPhysiology 2
1.3 RegulationofPPIs 3
1.4 StructuralFeaturesofPPIInterfaces 3
1.4.1 iNOSHomodimer 5
1.4.2 b-Catenin/Tcf4Complex 5
1.4.3 LEDGF/HIV-INComplex 6
1.4.4 HPVE1/E2Complex 7
1.4.5 IFN-a/IFNARComplex 8
1.4.6 TNF-aTrimer 9
1.5 IdentificationofPPIInhibitors 10
1.6 ConclusionsandOutlook 13
References 14
2 PredictionofIntra-andInterspeciesProtein–ProteinInteractions
FacilitatingSystemsBiologyStudies 21
SylviaSchleker,SeshanAnanthasubramanian,JudithKlein-Seetharaman,
andMadhaviK.Ganapathiraju
2.1 Introduction:RelevanceofInteractomeStudiestoDiseaseandDrug
Discovery 21
2.2 OurCurrentKnowledgeofInteractomesIdentifiedfrom
ExperimentsisIncomplete 23
2.3 ReliabilityofInteractionsIdentifiedExperimentally 24
2.4 ComputationalMethodsforPPIPrediction 27
2.4.1 ConservationofGeneNeighborhood 27
2.4.2 GeneFusion 28
2.4.3 Sequence-BasedCoevolution 28
j
VI Contents
2.4.4 PhylogeneticProfiling 28
2.4.5 GeneExpression 29
2.4.6 StructuralSimilarity 29
2.4.7 IntegrationApproaches 29
2.5 SourcesofBiologicalDatainUsetoPredictPPIs 30
2.6 SurveyofCurrentInteractomes 32
2.6.1 HumanIntraspeciesInteractomes 32
2.6.2 BacteriaIntraspeciesInteractomes 37
2.6.2.1 High-ThroughputExperimentalApproachestoIdentifyIntraspecies
BacterialInteractions 37
2.6.2.2 ModelingIntraspeciesBacterialInteractions 39
2.6.3 Bacteria–HumanInterspeciesInteractomes 40
2.6.3.1 ExperimentalApproachestoIdentifyBacteria–HumanPPIs 40
2.6.3.2 ModelingBacteria–HumanPPIs 40
2.6.4 Non-PPIIntraspeciesBacterialandBacteria–HumanInterspecies
InteractomeModels 41
2.6.5 Virus–HumanInterspeciesInteractomes 42
References 43
3 ModulatorsofProtein–ProteinInteractions:Importance
ofThree-Dimensionality 55
DavidC.FryandSung-SauSo
3.1 Introduction 55
3.2 Study 56
3.3 Discussion 58
3.4 Summary 61
References 61
4 ALeapintotheChemicalSpaceofProtein–ProteinInteraction
Inhibitors 63
BrunoO.Villoutreix,C.Labb(cid:1)e,DavidLagorce,GuillaumeLaconde,
andOlivierSperandio
4.1 Introduction 63
4.2 TypesofInteraction 64
4.3 PropertiesoftheInterface 65
4.4 OrthostericversusAllostericModulation 66
4.5 LeapintotheiPPIChemicalSpace 66
4.5.1 SeminalWorks 66
4.5.2 RoadtoaRationalizationoftheiPPIChemicalSpace 67
4.6 CaseStudy 68
4.6.1 VisualizingtheiPPIChemicalSpace 70
4.6.2 iPPIversusADME/ToxProperties 71
4.6.3 iPPIversusAromaticity 75
4.6.4 iPPIversusChemicalComplexity 77
j
Contents VII
4.6.5 iPPIversusMolecularShape 77
4.6.6 iPPIversusPotency 79
4.7 Conclusions 80
References 81
5 InteractiveTechnologiesforLeveragingtheKnownChemistry
ofAnchorResiduestoDisruptProteinInteractions 85
CarlosJ.Camacho,DavidR.Koes,andAlexanderS.D€omling
5.1 Introduction 85
5.2 DruggableSitesinPPIs 86
5.3 Structure-BasedLibraryDesign–APowerfulAlternative
toHigh-ThroughputScreening 87
5.4 NewMCRChemistrytoDesignPPIAntagonists 89
5.5 VirtualScreening 90
5.6 NewInteractiveModelingTechniquesforMedicinal
Chemists 93
5.7 NewIdeas:HitRateValidationofAnchor-CenteredScreening
ofp53/MDM2/4 95
5.8 Summary 96
References 97
6 SH3DomainsasDrugTargets 101
JamesLuccarelli,SamThompson,andAndrewD.Hamilton
6.1 Introduction 101
6.2 Structure 101
6.3 Variability 102
6.4 SH3BindingMotifs 104
6.4.1 ClassicalBindingMotifs 104
6.4.2 Tyrosine-ContainingMotifs 107
6.4.3 RxxKMotif 108
6.4.4 OtherBindingMotifsfromProteomicScreens 109
6.4.5 TertiaryInteractions 110
6.5 Selectivity 111
6.6 DrugTargetSelection 114
6.7 InhibitionStrategies:PeptideandPeptoid
Inhibitors 114
6.7.1 PeptideLigands 114
6.7.2 CombinatorialApproaches 115
6.7.3 PeptideDimers 116
6.7.4 ConstrainedPeptides 118
6.7.5 N-SubstitutedPeptoids 118
6.8 Small-MoleculeInhibitors 119
6.9 Conclusions 122
References 122
j
VIII Contents
7 p53/MDM2Antagonists:TowardsNongenotoxic
AnticancerTreatments 129
KareemKhoury,TadA.Holak,andAlexanderD€omling
7.1 Introduction 129
7.2 p53/MDM2PPIisCharacterizedbyManyCocrystal
Structures 130
7.3 Nutlins:First-In-ClassMDM2Antagonists 131
7.4 Johnson&Johnson:Benzodiazepines 133
7.5 Amgen:Chromenotriazolopyrimidines&Piperidones 137
7.6 UniversityofMichigan:Spirooxindole 148
7.7 UniversityofPittsburgh:UgiBasedCompounds 153
7.8 UniversityofNewcastle:SomeScaffoldsWithNoStructuralBiology
Information 155
7.9 Outlook 161
References 161
8 InhibitionofLFA-1/ICAMInteractionfortheTreatment
ofAutoimmuneDiseases 165
KevinM.GuckianandDanielM.Scott
8.1 Introduction 165
8.2 IntegrinStructureandActivation 166
8.3 DirectInhibitionoftheLFA-1/ICAMInteraction 168
8.4 AllostericInhibitorsoftheLFA-1/ICAMinteraction–IDASSite 171
8.4.1 Abbott/ICOS/BiogenSeries 171
8.4.2 BoehringerIngelheim/TanabeSeiyaku/Bristol-MyersSquibb
Series 178
8.5 Summary 183
References 183
9 ThePIFPocketofAGCKinases:ATargetSiteforAllostericModulators
andProtein–ProteinInteractionInhibitors 187
MatthiasEngel
9.1 Introduction 187
9.2 DiscoveryandPhysiologicalFunctionsofthePIFPocket 190
9.3 PropertiesofthePIFPocketRelevanttoDrug
Development 192
9.3.1 ThePIFPocketOffersthePotentialtoDevelopHighly
SelectiveLigands 192
9.3.2 MolecularInteractionsoftheNaturalHMPeptideLigands 193
9.3.3 AllostericMechanismofthePIFPocket 196
9.3.4 StructuralPlasticityofthePIFPocket 198
9.4 Small-MoleculePIFPocketLigands 199
9.4.1 AllostericActivatorsandPPIInhibitorsofPDK1 199
9.4.2 IdentificationofFirstHitCompoundsUsingaPharmacophore-Based
ScreeningApproach 200
j
Contents IX
9.4.3 CurrentStateofResearchonPIFPocket-DirectedPDK1
Modulators 203
9.4.4 AllostericInhibitors 207
9.5 PotentialSupportiveEffectsEnhancingtheCellularActivityofPIF
Pocket-BindingModulators 209
9.5.1 AllostericActivatorsofPDK1 209
9.5.2 PIFPocket-DirectedInhibitorsofAGCKinases 210
9.6 Conclusions 212
9.6.1 IsthePIFPocketaDruggableSite? 212
9.6.2 GeneralMedicinalChemistryAspectsand
Outlook 213
References 215
10 RetosibanandEpelsiban:PotentandSelectiveOrallyAvailable
OxytocinAntagonists 225
AlanD.BorthwickandJohnLiddle
10.1 Introduction 225
10.2 Aryl-2,5-DKPTemplateDiscoveryandInitialStructure–Activity
RelationshipStudies 227
10.3 SynthesisoftheRRRandRRS6-Indanyl-3-isobutyl-7-aryl-2,5-DKP
SecondaryAmides 231
10.4 ComparisonofCrystalStructuresofOxytocinand2,5-DKPs 231
10.5 PharmacokineticsandProperty-BasedDesign 232
10.6 InVivoPotencyof20,40-DiflurophenylDimethylamide22 235
10.7 SynthesisofTertiaryAmides 236
10.7.1 SynthesisofFive-andSix-MemberedHeterocyclic2,5-DKPs 237
10.8 SummaryofLeadOxytocinAntagonist 20,40-Diflurophenyl
Dimethylamide22 238
10.9 FurtherModifications,Five-andSix-MemberedHeterocyclic
Derivatives 238
10.10 Five-MemberedHeterocyclicDerivativesandRetosiban 239
10.10.1 OxytocinAntagonistActivityandSelectivityversusHuman
VasopressinReceptors 242
10.10.2 InVivoPotencyandSynthesis 243
10.11 SummaryofLeadOxytocinAntagonistRetosiban56 244
10.12 Six-MemberedHeterocyclicDerivativesandEpelsiban 244
10.12.1 MonosubstitutedPyridylisoButylDerivatives 246
10.12.2 ModificationofisoButylin60-MePyridylDerivatives 246
10.12.3 Dimethylpyridyl(S)-sec-ButylAmides 246
10.12.4 FurtherEvaluationof20,60-Dimethyl-30-pyridineMorpholine
Amide77 250
10.13 SummaryofLeadOxytocinAntagonistEpelsiban77 252
10.14 ComparisonofLeadCompounds 252
10.15 Conclusions 254
References 254
j
X Contents
11 PeptidicInhibitorsofProtein–ProteinInteractionsforCellAdhesion
Receptors:RGDPeptidesandBeyond 257
CarlosMas-MorunoandHorstKessler
11.1 Introduction 257
11.2 FromtheDiscoveryoftheRGDMotifinFNtotheFirstSelective
CyclicRGDPeptide 258
11.2.1 RGDSequence,Integrins,andReceptorSelectivity 258
11.2.2 ConceptofSpatialScreeninginCyclicRGDPeptides 261
11.2.3 ConformationalAspectsandSelectivityofc(RGDfV) 263
11.2.4 PharmacophoricRequirementsofc(RGDfV)toBinda b 265
v 3
11.3 N-Methylationofc(RGDfV):CilengitideandBeyond 267
11.3.1 ConceptofN-Methylation 267
11.3.2 N-MethylScanofc(RGDV):Synthesis,BiologicalActivity,and
StructuralConsiderationsofCilengitide 268
11.3.3 BeyondCilengitide:di-N-MethylatedAnalogsofc(RGDfV)anda b
v 3
Selectivity 271
11.4 isoDGRSequenceasaNewIntegrin-BindingMotif 274
11.4.1 FormationofisoAspResiduesinPeptidesandProteins 274
11.4.2 NGRDeamidationtoisoDGRYieldsaNewIntegrin-Binding
Motif 275
11.4.3 DesignofCyclicPeptidesContainingtheisoDGRMotifas
NewIntegrinAntagonists 276
11.4.4 ReceptorSelectivityofCyclicisoDGRPeptides 279
11.5 Conclusions 281
References 282
12 REPLACEStrategyforGeneratingNon-ATP-CompetitiveInhibitors
ofCellCycleProteinKinases 291
CampbellMcInnes
12.1 Introduction 291
12.2 InhibitionofCDKsThroughtheCyclinGroove 291
12.3 InhibitorsofPLKs 298
12.3.1 PBDomain 298
12.4 Conclusions 301
References 302
Index 305