Ligand Design for G Protein-coupled Receptors (Methods and Principles in Medicinal Chemistry)

276 Pages·2006·4.283 MB·English

by  Didier Rognan, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers

LigandDesign
forGProtein-coupledReceptors
Editedby
DidierRognan
LigandDesignforGProtein-coupledReceptors.EditedbyDidierRognan
Copyright(cid:1)2006WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-31284-6
Methods and Principles in Medicinal Chemistry
EditedbyR.Mannhold,H.Kubinyi,G.Folkers
EditorialBoard
H.-D.Höltje,H.Timmerman,J.Vacca,H.vandeWaterbeemd,T.Wieland
Previous Volumes ofthis Series:
Th.Dingermann,D.Steinhilber, O.Kappe,A.Stadler
G.Folkers(eds.)
Microwaves in Organic
Molecular Biology
andMedicinal Chemistry
in Medicinal Chemistry
Vol.25
Vol.21
2005,ISBN3-527-31210-2
2004,ISBN3-527-30431-2
W.Bannwarth,B.Hinzen(eds.)
H.Kubinyi,G.Müller(ed.)
Combinatorial Chemistry
Chemogenomics
Vol.26
in DrugDiscovery
2005,ISBN3-527-30693-5
Vol.22
2004,ISBN3-527-30987-X G.Cruciani(ed.)
Molecular Interaction Fields
T.I.Oprea(ed.)
Vol.27
Chemoinformatics
2005,ISBN3-527-31087-8
in DrugDiscovery
Vol.23 M.Hamacher,K.Marcus,K.Stühler,A.vanHall,
B.Warscheid,H.E.Meyer(eds.)
2005,ISBN3-527-30753-2
Proteomics in DrugDesign
R.Seifert,T.Wieland(eds.)
Vol.28
G-ProteinCoupled Receptors
2005,ISBN3-527-31226-9
as DrugTargets
Vol.24 D.J.Triggle,M.Gopalakrishnan,D.Rampe,
W.Zheng
2005,ISBN3-527-30819-9
Voltage-Gated Ion Channels
as DrugTargets
Vol.29
2006,ISBN3-527-31258-7
Ligand Design
for G Protein-coupled Receptors
Edited by
Didier Rognan
SeriesEditors (cid:2) AllbookspublishedbyWiley-VCHarecarefullypro-
duced.Nevertheless,authors,editors,andpublisherdo
Prof.Dr.RaimundMannhold notwarranttheinformationcontainedinthesebooks,
BiomedicalResearchCenter includingthisbook,tobefreeoferrors.Readersare
MolecularDrugResearchGroup advisedtokeepinmindthatstatements,data,illustra-
Heinrich-Heine-Universität tions,proceduraldetailsorotheritemsmayinadver-
Universitätsstrasse1 tentlybeinaccurate.
40225Düsseldorf
Germany LibraryofCongressCardNo.:appliedfor
[email protected]
BritishLibraryCataloguing-in-PublicationData:
Prof.Dr.HugoKubinyi Acataloguerecordforthisbookisavailablefromthe
Donnersbergstrasse9 BritishLibrary
67256WeisenheimamSand
Germany Bibliographicinformationpublishedby
[email protected] DieDeutscheBibliothek
DieDeutscheBibliothekliststhispublicationinthe
Prof.Dr.GerdFolkers DeutscheNationalbibliografie;detailedbibliographic
CollegiumHelveticum dataisavailableintheInternetathttp://dnb.ddb.de.
STW/ETHZürich
8092Zürich 2006WILEY-VCHVerlagGmbH&Co.KGaA,
Switzerland Weinheim,Germany
[email protected]
Allrightsreserved(includingthoseoftranslationinto
otherlanguages).Nopartofthisbookmayberepro-
VolumeEditor ducedinanyform–byphotoprinting,microfilm,or
anyothermeans–nortransmittedortranslatedinto
Prof.Dr.DidierRognan amachinelanguagewithoutwrittenpermissionfrom
LaboratoiredePharmacochimie thepublishers.Registerednames,trademarks,etc.
delaCommunicationCellulaire usedinthisbook,evenwhennotspecificallymarked
CNRSUMR7175-LC1 assuch,arenottobeconsideredunprotectedbylaw.
InstitutGilbertLaustriat
BoulevardSébastienBrant CoverDesign SCHULZGrafikDesign,
67412Illkirch Fußgönheim
France Composition ProSatzUnger,Weinheim
Printing betz-druckGmbH,Darmstadt
Bookbinding J.SchäfferGmbH,Grünstadt
PrintedintheFederalRepublicofGermany
Printedonacid-freepaper
ISBN-13:978-3-527-31284-9
ISBN-10:3-527-31284-6
V
Contents
Preface XIII
1 GProtein-coupledReceptorsintheHumanGenome 1
RobertFredrikssonandHelgiB.Schiöth
1.1 Introduction 1
1.2 TheAdhesionFamily 2
1.3 TheSecretinFamily 5
1.4 TheFrizzled/Taste2Family 5
1.4.1 TheFrizzledReceptorCluster 6
1.4.2 TheTaste2ReceptorCluster 8
1.5 TheGlutamateFamily 8
1.6 TheRhodopsinFamily 11
1.6.1 TheRhodopsin(cid:1)-Group 11
1.6.1.1 TheProstaglandinReceptorCluster 11
1.6.1.2 TheAmineReceptorCluster 12
1.6.1.3 TheOpsinReceptorCluster 13
1.6.1.4 TheMelatoninReceptorCluster 14
1.6.1.5 TheMECAReceptorCluster 14
1.6.1.6 OtherRhodopsin(cid:1)-Receptors 14
1.6.2 Rhodopsin(cid:2)-Group 15
1.6.3 Rhodopsin(cid:3)-Group 15
1.6.3.1 TheSOGReceptorCluster 16
1.6.3.2 TheMelanocyteConcentratingHormoneReceptorCluster 17
1.6.3.3 TheChemokineReceptorCluster 18
1.6.3.4 OtherRhodopsin(cid:3)-Receptors 18
1.6.4 TheRhodopsin(cid:4)-Group 18
1.6.4.1 TheMAS-relatedReceptorCluster 18
1.6.4.2 TheGlycoproteinReceptorCluster 20
1.6.4.3 TheCoagulationFactorReceptorCluster 20
1.6.4.4 ThePurinergicReceptorCluster 20
1.6.4.5 TheOlfactoryReceptorCluster 20
1.6.4.6 OtherRhodopsin(cid:1)-Receptors 20
LigandDesignforGProtein-coupledReceptors.EditedbyDidierRognan
Copyright(cid:1)2006WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-31284-6
VI Contents
1.7 OtherGPCRs 21
1.8 FuturePerspective 21
References 23
2 WhyGProtein-coupledReceptorsDatabasesareNeeded 27
JacquesHaiech,Jean-LucGalzi,Marie-ClaudeKilhoffer,MarcelHibert,
andDidierRognan
2.1 Introduction 27
2.2 ANon-exhaustiveListoftheGPCRDataModels 27
2.3 UsingtheCentralDogmaofBiology 28
2.4 UsingtheTreeofLife 30
2.5 UsingaChemogenomicApproach 35
2.6 Conclusion 38
References 38
3 ANovelDrugScreeningAssayforGProtein-coupledReceptors 51
BrianF.O’Dowd,XiaodongJi,MohammadAlijaniaram,TuanNguyen,
andSusanR.George
3.1 Introduction 51
3.1.1 History 51
3.1.2 NuclearTranslocationofEndogenousGPCRs 52
3.1.3 TheMOCAMethod 52
3.2 TheMOCAStrategyDemonstratedwiththeD1DopamineReceptor 53
3.2.1 DevelopmentoftheAssay 53
3.2.2 Concentration-dependentAntagonistBlockadeofNuclearTransport 55
3.2.3 MeasurementofReceptorCellSurfaceExpression:AntagonistBinding
ofReceptorsatCellSurface 55
3.3 DevelopmentofQuantitativeMethodologySuitableforHighThroughput
Analysis 56
3.3.1 NuclearTranslocationofOrphanGPCRs 58
3.4 DiscussionoftheMOCAMethod 58
3.5 Conclusion 59
References 60
4 ImportanceofGPCRDimerizationforFunction:
TheCaseoftheClassCGPCRs 61
LaurentPrézeau,CyrilGoudet,PhilippeRondard,andJean-PhilippePin
4.1 Introduction 61
4.2 ClassCGPCRsareMultidomainProteins 62
4.2.1 TheVFT 63
4.2.2 TheCRD 64
4.2.3 TheHD 65
4.2.4 C-Tail 66
4.3 ClassCGPCRsareConstitutiveDimers 66
Contents VII
4.4 AgonistsActivateClassCGPCRsbyStabilizingtheClosedState
oftheVFT 67
4.5 DimericFunctioningoftheDimerofVFTs 68
4.5.1 AgonistStoichiometry:SymmetryorAsymmetry? 70
4.6 TheHeptahelicalDomain,theTargetofPositiveandNegativeAllosteric
Modulators,BehavesinaMannerSimilartoRhodopsin-likeClassA
GPCRs 71
4.7 AllostericCouplingBetweentheExtracellularandHeptahelicalDomains
withintheDimer 73
4.7.1 MolecularDeterminantsoftheCouplingBetweentheVFT
andtheHD 73
4.7.2 Cis-andTrans-activationCanExistwithinClassCGPCRs 74
4.8 AsymmetricFunctioningoftheHDDimer 75
4.9 Conclusion 76
References 77
5 MolecularMechanismsofGPCRActivation 83
RobertP.BywaterandPaulDenny-Gouldson
5.1 StructureofGProtein-coupledReceptors 83
5.2 ActivationofGPCRsbyEndogenousLigands:TheConceptofReceptor
Agonism 84
5.3 DistinctionBetweenOrthostericandAllostericLigands 84
5.4 OnlyaFewReceptorTypesareKnowntoPossessanEndogenous
Antagonist 85
5.5 ConstitutivelyActiveGPCRs 86
5.6 MechanismofGPCRActivation:TheActive/Inactive“Switch” 86
5.7 GPCRDimerization 88
5.8 ActivationofGProteins 89
5.9 InteractionBetweenGPCRsandGProteins 90
5.10 Conclusions 91
References 92
6 AllostericPropertiesandRegulationofGProtein-coupledReceptors 99
Jean-LucGalzi,EmelineMaillet,SandraLecat,MurielHachet-Haas,
JacquesHaiech,MarcelHibert,andBrigitteIlien
6.1 Introduction 99
6.2 MultipleConformationsandSignalingPathwaysofGProtein-coupled
Receptors 101
6.2.1 BiophysicalApproachestoMonitoringConformationalChanges
ofGProtein-coupledReceptors 102
6.3 AllostericModulatorsofGProtein-coupledReceptors 105
6.4 WhereDoAllostericModulatorsBindonGPCRs? 107
6.5 FutureChallengesforAllostericModulationofGPCRs 111
References 112
VIII Contents
7 ChemogenomicsApproachestoLigandDesign 115
ThomasKlabunde
7.1 IntroductiontoChemogenomics:SimilarReceptorsBindSimilar
Ligands 115
7.2 FocusedLibrariesandScreeningCollectionsDirectedAgainst
GPCRs 117
7.2.1 PhysicochemicalProperty-basedSelectionofGPCRScreeningSets 118
7.2.2 PharmacophoreandMolecularDescriptorsforGPCRDirected
Libraries 118
7.2.3 Privileged-fragment-basedGPCR-directedLibraries 120
7.2.4 GPCRCollectionandSubfamily-directedLibraryDesign 121
7.3 UnderstandingMolecularRecognition:ImpactonGPCRLigand
Design 124
7.3.1 SitesforLigandRecognitionwithinBiogenic-amine-bindingandOther
GPCRs 125
7.3.2 DesignofGPCR-directedLibrariesUsing“Motifs”and“Themes“ 127
7.3.3 “Chemoprints”forRecognitionofGPCR-privilegedFragments 127
7.3.4 MolecularInteractionModelsbyProteochemometrics 131
7.4 Outlook 132
References 133
8 StrategiesfortheDesignofpGPCR-targetedLibraries 137
NikolayP.Savchuk,SergeyE.Tkachenko,andKonstantinV.Balakin
8.1 Introduction 137
8.1.1 PeptidergicGPCRs:BriefOverview 137
8.1.2 EndogenousLigandsforpGPCRs 140
8.1.3 PotentialTherapeuticTargetsofpGPCRs 140
8.2 ApproachestotheDesignofpGPCR-targetedLibraries 141
8.2.1 ProblemsinDrugDiscoveryDirectedTowardspGPCRs 143
8.2.2 DockingandPharmacophore-basedDesign 146
8.2.3 Knowledge-basedDataMiningApproaches 148
8.2.4 ChemogenomicsApproaches 149
8.2.5 IncorporationofSpecificBiomolecularRecognitionMotifs 149
8.2.5.1 PrivilegedStructures 150
8.2.5.2 MimeticsofthePeptideSecondaryStructureElements 154
8.3 SynthesisofpGPCR-focusedLibraries:ExampleofaPractical
Methodology 156
8.4 Conclusions 159
References 160
Contents IX
9 Ligand-basedRationalDesign:VirtualScreening 165
DavidE.ClarkandChristopherHiggs
9.1 Introduction 165
9.2 WhyUseLigand-basedVirtualScreening? 166
9.2.1 Speed 166
9.2.2 Applicability 166
9.2.3 Complementarity 166
9.3 OverviewofLigand-basedVirtualScreening 167
9.3.1 StartingPoints 167
9.3.2 ChemicalStructureDatabases 167
9.3.3 DatabaseSearchTechniques 168
9.3.3.1 2-DSubstructureSearching 168
9.3.3.2 2-DSimilaritySearching 169
9.3.3.3 3-DSubstructureSearching 170
9.3.3.4 3-DSimilaritySearching 170
9.3.3.5 PharmacophoreSearching 170
9.4 SuccessfulApplicationsofLigand-basedVirtualScreeningfor
GPCRs 170
9.4.1 SomatostatinAgonists 171
9.4.2 MuscarinicM ReceptorAntagonists 172
3
9.4.3 UrotensinIIAntagonists 174
9.4.4 Melanin-concentratingHormone-1ReceptorAntagonists 176
9.4.5 GrowthHormoneSecretagogueReceptorAgonists 178
9.5 Conclusions 179
References 180
10 3-DStructureofGProtein-coupledReceptors 183
LeonardoPardo,XavierDeupi,CedricGovaerts,andMercedesCampillo
10.1 Introduction 183
10.2 ClassificationofGProtein-coupledReceptors 185
10.3 TheExtracellularN-terminalDomainofGProtein-coupled
Receptors 185
10.4 SequenceAnalysesofthe7TMSegmentsoftheRhodopsinFamily
ofGProtein-coupledReceptors 185
10.5 TheConformationofPro-kinkedTransmembrane(cid:1)-Helices 186
10.6 HelixDeformationintheRhodopsinFamilyofGProtein-coupled
Receptors 187
10.6.1 TransmembraneHelix1 187
10.6.2 TransmembraneHelix2 188
10.6.3 TransmembraneHelix3 190
10.6.4 TransmembraneHelix4 190
10.6.5 TransmembraneHelix5 190
10.6.6 TransmembraneHelix6 192
10.6.7 TransmembraneHelix7 193
10.7 StructuralandFunctionalRoleofInternalWaterMolecules 193