Structure-based Design of Drugs and Other Bioactive Molecules: Tools and Strategies

476 Pages·2014·10.936 MB·English

by  Arun K. Ghosh, Sandra Gemma

Arun K. Ghosh and Sandra Gemma
Structure-based Design
of Drugs and
Other Bioactive Molecules
Tools and Strategies

ArunK.GhoshandSandraGemma
Structure-basedDesignofDrugsand
OtherBioactiveMolecules
RelatedTitles
Li,J.J.,Corey,E.J.(eds.)
DrugDiscovery
Practices,Processes,andPerspectives
2013
ISBN:978-0-470-94235-2(Alsoavailable
inelectronicformats)
Brown,N.(ed.)
ScaffoldHoppinginMedicinalChemistry
2014
ISBN:978-3-527-33364-6(Alsoavailable
inelectronicformats)
Schneider,G.(ed.)
DenovoMolecularDesign
2014
ISBN:978-3-527-33461-2(Alsoavailableinelectronicformats)
Young,D.C.
ComputationalDrugDesign
AGuideforComputationalandMedicinalChemists(withCD-Rom)
2009
PrintISBN:978-0-470-12685-1(Alsoavailableinelectronicformats)
Arun K. Ghosh and Sandra Gemma
Structure-based Design of Drugs and
Other Bioactive Molecules
Tools and Strategies
TheAuthors AllbookspublishedbyWiley-VCHarecarefully
produced.Nevertheless,authors,editors,and
Prof.Dr.ArunK.Ghosh publisherdonotwarranttheinformationcontained
PurdueUniversity inthesebooks,includingthisbook,tobefreeof
DepartmentofChemistry errors.Readersareadvisedtokeepinmindthat
andDepartmentofMedicinalChemistry statements,data,illustrations,proceduraldetailsor
560OvalDrive otheritemsmayinadvertentlybeinaccurate.
WestLatayette,IN
UnitedStates LibraryofCongressCardNo.:appliedfor
BritishLibraryCataloguing-in-PublicationData
Prof.Dr.SandraGemma
Acataloguerecordforthisbookisavailablefromthe
UniversitàdegliStudiSiena
BritishLibrary.
DipartimentodiBiotecnologie,Chimicae
Farmacia BibliographicinformationpublishedbytheDeutsche
viaAldoMoro2 Nationalbibliothek
53100Siena TheDeutscheNationalbibliothekliststhis
Italy publicationintheDeutscheNationalbibliografie;
detailed bibliographicdataareavailableonthe
Internet at < http:// dnb.d-nb.d e> .
#2014Wiley-VCHVerlagGmbH&Co.KGaA,
Boschstr.12,69469Weinheim,Germany
Allrightsreserved(includingthoseoftranslationinto
otherlanguages).Nopartofthisbookmaybe
reproducedinanyform–byphotoprinting,
microfilm,oranyothermeans–nortransmittedor
translatedintoamachinelanguagewithoutwritten
permissionfromthepublishers.Registerednames,
trademarks,etc.usedinthisbook,evenwhennot
specificallymarkedassuch,arenottobeconsidered
unprotectedbylaw.
PrintISBN: 978-3-527-33365-3
ePDFISBN: 978-3-527-66524-2
ePubISBN: 978-3-527-66523-5
MobiISBN: 978-3-527-66522-8
oBookISBN: 978-3-527-66521-1
CoverDesign BlueseaDesign,McLeeseLake,
Canada
Typesetting ThomsonDigital,Noida,India
PrintingandBinding MarkonoPrintMediaPteLtd,
Singapore
Printedonacid-freepaper
j
V
Contents
Preface XIII
1 FromTraditionalMedicinetoModernDrugs:Historical
PerspectiveofStructure-BasedDrugDesign 1
1.1 Introduction 1
1.2 DrugDiscoveryDuring1928–1980 1
1.3 TheBeginningofStructure-BasedDrugDesign 6
1.4 Conclusions 12
References 13
PartOne Concepts,Tools,Ligands,andScaffoldsforStructure-Based
DesignofInhibitors 19
2 DesignofInhibitorsofAsparticAcidProteases 21
2.1 Introduction 21
2.2 DesignofPeptidomimeticInhibitorsofAsparticAcidProteases 22
2.3 DesignofStatine-BasedInhibitors 24
2.4 DesignofHydroxyethyleneIsostere-BasedInhibitors 29
2.5 DesignofInhibitorswithHydroxyethylamineIsosteres 35
2.5.1 SynthesisofOpticallyActivea-AminoalkylEpoxide 37
2.6 Designof(Hydroxyethyl)urea-BasedInhibitors 40
2.7 (Hydroxyethyl)sulfonamide-BasedInhibitors 42
2.8 DesignofHeterocyclic/NonpeptidomimeticAspartic
AcidProteaseInhibitors 42
2.8.1 Hydroxycoumarin-andHydroxypyrone-BasedInhibitors 44
2.8.2 DesignofSubstitutedPiperidine-BasedInhibitors 46
2.8.3 DesignofDiaminopyrimidine-BasedInhibitors 50
2.8.4 DesignofAcylGuanidine-BasedInhibitors 51
2.8.5 DesignofAminopyridine-BasedInhibitors 53
2.8.6 DesignofAminoimidazole-andAminohydantoin-BasedInhibitors 53
2.9 Conclusions 56
References 56
VIjContents
3 DesignofSerineProteaseInhibitors 67
3.1 Introduction 67
3.2 CatalyticMechanismofSerineProtease 67
3.3 TypesofSerineProteaseInhibitors 67
3.4 HalomethylKetone-BasedInhibitors 69
3.5 DiphenylPhosphonate-BasedInhibitors 70
3.6 TrifluoromethylKetoneBasedInhibitors 73
3.6.1 SynthesisofTrifluoromethylKetones 76
3.7 PeptidylBoronicAcid-BasedInhibitors 78
3.7.1 Synthesisofa-AminoalkylBoronicAcidDerivatives 83
3.8 Peptidyla-Ketoamide-anda-Ketoheterocycle-BasedInhibitors 85
3.8.1 Synthesisofa-Ketoamideanda-KetoheterocyclicTemplates 90
3.9 DesignofSerineProteaseInhibitorsBasedUponHeterocycles 93
3.9.1 Isocoumarin-DerivedIrreversibleInhibitors 94
3.9.2 b-Lactam-DerivedIrreversibleInhibitors 95
3.10 Reversible/NoncovalentInhibitors 97
3.11 Conclusions 104
References 105
4 DesignofProteasomeInhibitors 113
4.1 Introduction 113
4.2 CatalyticMechanismof20SProteasome 113
4.3 ProteasomeInhibitors 114
4.3.1 DevelopmentofBoronateProteasomeInhibitors 115
4.3.2 Developmentofb-LactoneNaturalProduct-BasedProteasome
Inhibitors 116
4.3.3 DevelopmentofEpoxyKetone-DerivedInhibitors 118
4.3.4 NoncovalentProteasomeInhibitors 120
4.4 Synthesisofb-LactoneScaffold 121
4.5 SynthesisofEpoxyKetoneScaffold 123
4.6 Conclusions 126
References 126
5 DesignofCysteineProteaseInhibitors 131
5.1 Introduction 131
5.2 DevelopmentofCysteineProteaseInhibitorswithMichael
Acceptors 132
5.3 DesignofNoncovalentCysteineProteaseInhibitors 136
5.4 Conclusions 140
References 140
6 DesignofMetalloproteaseInhibitors 143
6.1 Introduction 143
6.2 DesignofMatrixMetalloproteaseInhibitors 144
ContentsjVII
6.3 DesignofInhibitorsofTumorNecrosisFactor-a-Converting
Enzymes 150
6.4 Conclusions 152
References 152
7 Structure-BasedDesignofProteinKinaseInhibitors 155
7.1 Introduction 155
7.2 ActiveSiteofProteinKinases 155
7.3 CatalyticMechanismofProteinKinases 156
7.4 DesignStrategyforProteinKinaseInhibitors 156
7.5 NatureofKinaseInhibitorsBaseduponBinding 160
7.5.1 TypeIKinaseInhibitorsandTheirDesign 160
7.5.2 TypeIIKinaseInhibitorsandTheirDesign 164
7.5.3 AllostericKinaseInhibitorsandTheirDesign 168
7.5.4 CovalentKinaseInhibitorsandTheirDesign 172
7.6 Conclusions 177
References 177
8 ProteinX-RayCrystallographyinStructure-BasedDrugDesign 183
8.1 Introduction 183
8.2 ProteinExpressionandPurification 184
8.3 SynchrotronRadiation 185
8.4 StructuralBiologyinFragment-BasedDrugDesign 186
8.5 SelectedExamplesofFragment-BasedStudies 187
8.6 Conclusions 196
References 197
9 Structure-BasedDesignStrategiesforTargetingG-Protein-Coupled
Receptors(GPCRs) 199
9.1 Introduction 199
9.2 High-ResolutionStructuresofGPCRs 200
9.3 VirtualScreeningAppliedtotheb2-Adrenergic
Receptor 201
9.4 Structure-BasedDesignofAdenosineA2AReceptor
Antagonists 204
9.5 Structure-GuidedDesignofCCR5Antagonists 207
9.5.1 DevelopmentofMaravirocfromHTSLeadMolecules 207
9.5.2 ImprovementofAntiviralActivityandReductionof
CytochromeP450Activity 208
9.5.3 ReductionofhERGActivityandOptimizationofPharmacokinetic
Profile 209
9.5.4 OtherCCR5Antagonists 213
9.6 Conclusion 213
References 213
VIIIjContents
PartTwo Structure-BasedDesignofFDA-ApprovedInhibitorDrugsandDrugs
UndergoingClinicalDevelopment 217
10 Angiotensin-ConvertingEnzymeInhibitorsfortheTreatment
ofHypertension:DesignandDiscoveryofCaptopril 219
10.1 Introduction 219
10.2 DesignofCaptopril:theFirstClinicallyApproved
Angiotensin-ConvertingEnzymeInhibitor 220
10.3 StructureofAngiotensin-ConvertingEnzyme 225
10.4 DesignofACEInhibitorsContainingaCarboxylateas
ZincBindingGroup 228
10.5 ACEInhibitorsBearingPhosphorus-BasedZincBindingGroups 231
10.5.1 Phosphonamidate-BasedInhibitors 232
10.5.2 PhosphonicandPhosphinicAcidDerivatives:thePathto
Fosinopril 233
10.6 Conclusions 234
References 235
11 HIV-1ProteaseInhibitorsfortheTreatmentofHIVInfectionandAIDS:
DesignofSaquinavir,Indinavir,andDarunavir 237
11.1 Introduction 237
11.2 StructureofHIVProteaseandDesignofPeptidomimeticInhibitors
ContainingTransition-StateIsosteres 239
11.3 Saquinavir:theFirstClinicallyApprovedHIV-1ProteaseInhibitor 241
11.4 Indinavir:anHIVProteaseInhibitorContainingthe
HydroxyethyleneTransition-StateIsostere 246
11.5 DesignandDevelopmentofDarunavir 251
11.6 DesignofCyclicEtherTemplatesinDrugDiscovery 252
11.7 InvestigationofCyclicSulfonesasP Ligands 255
2
11.8 DesignofBis-tetrahydrofuranandOtherBicyclicP Ligands 257
2
11.9 The“BackboneBindingConcept”toCombatDrugResistance:
InhibitorDesignStrategyPromotingExtensiveBackbone
HydrogenBondingfromS toS 0Subsites 259
2 2
11.10 DesignofDarunavirandOtherInhibitorswithClinical
Potential 263
11.11 Conclusions 266
References 266
12 ProteinKinaseInhibitorDrugsforTargetedCancerTherapy:Design
andDiscoveryofImatinib,Nilotinib,Bafetinib,andDasatinib 271
12.1 Introduction 271
12.2 EvolutionofKinaseInhibitorsasAnticancerAgents 272
12.3 TheDiscoveryofImatinib 274
12.4 Imatinib:theStructuralBasisofSelectivity 275
12.5 PharmacologicalProfileandClinicalDevelopment 278