Drug Selectivity: An Evolving Concept in Medicinal Chemistry

522 Pages·2018·16.129 MB·English

by  Norbert Handler, Helmut Buschmann, Raimund Mannhold, Jörg Holenz

EditedbyNorbertHandler
andHelmutBuschmann
DrugSelectivity
MethodsandPrinciplesinMedicinalChemistry
EditedbyR.Mannhold,H.Buschmann,JörgHolenz
EditorialBoard
J.Holenz,H.Kubinyi,H.Timmerman,H.vandeWaterbeemd,JohnBondoHansen
PreviousVolumesofthisSeries:
Vaughan,T.,Osbourn,J.,andJalla,B. Keserü,G.M.andSwinney,D.C.(Eds.)
ProteinTherapeutics KineticsandThermodynamicsof
DrugBinding
2017
ISBN:978-3-527-34086-6 2015
Vol.71
ISBN:978-3-527-33582-4
Vol.65
Ecker,G.F.,Clausen,R.P.,andSitte,H.H.(Eds.)
Pfannkuch,F.andSuter-Dick,L.(Eds.)
TransportersasDrugTargets
PredictiveToxicology
2017
ISBN:978-3-527-33384-4 FromVisiontoReality
Vol.70
2014
ISBN:978-3-527-33608-1
Martic-Kehl,M.I.andSchubiger,P.A.(Eds.) Vol.64
AnimalModelsforHumanCancer
Kirchmair,J.(Ed.)
DiscoveryandDevelopmentofNovelTherapeutics
DrugMetabolismPrediction
2017
ISBN:978-3-527-33997-6
2014
Vol.69
ISBN:978-3-527-33566-4
Vol.63
Holenz,Jörg(Ed.)
LeadGeneration Vela,J.M.,Maldonado,R.,andHamon,M.(Eds.)
MethodsandStrategies InvivoModelsforDrugDiscovery
2016
2014
ISBN:978-3-527-33329-5
ISBN:978-3-527-33328-8
Vol.68
Vol.62
Erlanson,D.A.andJahnke,W.(Eds.)
Liras,S.andBell,A.S.(Eds.)
Fragment-basedDrugDiscovery
PhosphodiesterasesandTheir
LessonsandOutlook Inhibitors
2015
ISBN:978-3-527-33775-0 2014
Vol.67 ISBN:978-3-527-33219-9
Vol.61
Urbán,L.,Patel,V.F.,andVaz,R.J.(Eds.)
AntitargetsandDrugSafety
2015
ISBN:978-3-527-33511-4
Vol.66
EditedbyNorbertHandlerandHelmutBuschmann
Drug Selectivity
AnEvolvingConceptinMedicinalChemistry
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v
Contents
Preface xiii
APersonalForeword xv
PartI Introduction 1
1 PolypharmacologyinDrugDiscovery 3
OscarMéndez-Lucio,J.JesúsNaveja,HugoVite-Caritino,
FernandoD.Prieto-Martínez,andJoséL.Medina-Franco
1.1 Polypharmacology 3
1.2 MultitargetversusTarget-SpecificDrugs 5
1.2.1 “MasterKeyCompounds” 5
1.2.2 SafetyPanels 8
1.3 PolypharmacologyandRelatedConceptsinDrugDiscovery 11
1.3.1 DrugRepurposing 11
1.3.2 CombinationofDrugs 12
1.3.3 InVivoTesting 12
1.4 Polypharmacology(andPolypharmacy):CaseStudies 13
1.4.1 PolypharmacologyinEpigenetics 13
1.4.2 ChartingtheEpigeneticRelevantChemicalSpace 14
1.4.3 PolypharmacyfortheTreatmentofHIVInfections 15
1.5 ComputationalStrategiestoExplorePolypharmacology 15
1.5.1 Chemogenomics:IntersectionofChemicalandBiologicalSpaces 16
1.5.2 Structure–MultipleActivityRelationships 17
1.5.3 ProteochemometricModeling 19
1.5.4 TargetFishing 19
1.5.5 DataMiningofSideEffectsandInteractionsforDrug
Repurposing 20
1.5.6 SystemsPharmacology 21
1.5.7 PolypharmacologyFingerprints 21
1.6 SummaryConclusions 21
Acknowledgments 22
References 22
vi Contents
PartII SelectivityofMarketedDrugs 31
2 KinaseInhibitors 33
PengWu,MichaelGivskov,andThomasE.Nielsen
2.1 Overview 33
2.2 KinaseProfiling 38
2.3 DefinitionandQuantificationofSelectivityLevels 40
2.4 SelectivityofApprovedKinaseInhibitors 43
2.4.1 Non-covalentTypeIandTypeIISMKIs 45
2.4.2 AllostericSMKIs 47
2.4.3 LipidKinaseInhibitor 48
2.4.4 CovalentInhibitors 48
2.5 ConclusionandPerspective 48
Acknowledgment 49
References 49
3 RepositioningofDrug–NewIndicationsforMarketed
Drugs 55
RenKongandStephenT.Wong
3.1 Introduction 55
3.2 NewUsesfromAdverseEffects 57
3.2.1 DapoxetineforPrematureEjaculation 57
3.2.2 SildenafilforErectileDysfunction 58
3.3 NewUsesBasedonKnownMechanismofAction 58
3.3.1 DuloxetineforStressUrinaryIncontinence(SUI) 58
3.3.2 ThalidomideforErythemaNodosumLeprosum(ENL)andMultiple
Myeloma 59
3.4 NewUsesfromGenome,Network,andSignalPathwayAnalysis 59
3.4.1 IdentificationofSunitinibandDasatinibforBreastCancerBrain
Metastasis 59
3.5 NewUsesBasedonNewTargetIdentification(Off-TargetEffects) 62
3.5.1 AntidepressantDrug,Amoxapine,forAlleviatingCancerDrug
ToxicityofIrinotecan 62
3.6 ComputationalandSystematicDrugRepositioning 64
3.6.1 MethodsBasedonKnowledgeofSideEffects 64
3.6.2 MethodsBasedonTranscriptomicsData(TranscriptionalProfile) 65
3.6.3 MethodsBasedonGenome-WideAssociationStudy(GWAS) 66
3.6.4 MethodsBasedonNetworkandPathwaysAnalysis 66
3.6.5 MethodsBasedonOff-TargetEffects 67
3.7 Perspective 68
Acknowledgment 73
References 73
4 DiscoveryTechnologiesforDrugRepurposing 79
NaiemT.Issa,StephenW.Byers,andSivanesanDakshanamurthy
4.1 Introduction 79
4.2 BiologicalDrugScreeningMethods 79
Contents vii
4.2.1 PhenotypicScreening 79
4.2.1.1 Animal-BasedScreening 80
4.2.1.2 Cell-BasedScreening 80
4.2.2 Target-BasedScreening 81
4.3 InsilicoToolsforDrugRepurposing 82
4.3.1 Docking 82
4.3.2 Chemoinformatics 83
4.3.3 ProteinBindingSite 84
4.3.4 CombiningDrug-CentricwithProtein-CentricApproaches 86
4.3.5 NetworkPharmacology 86
4.3.6 MiningofBigData 88
4.4 Conclusion 89
References 90
PartIII UnselectiveDrugsinDrugDiscovery 101
5 PersonalizedMedicine 103
ChristianNoeandVolkerBaumann
5.1 RootsofPersonalizedMedicine 103
5.2 TheReturnoftheActivePharmaceuticalIngredients(APIs) 104
5.3 SystemsPharmacology 105
5.4 ThePatientintheFocusofResearch 107
5.5 PersonalizedTherapy 107
5.6 GeneTherapy 108
5.7 RegenerativeMedicine 110
5.8 IndividualizedMedicines 110
5.9 StratifiedMedicines 112
5.10 DrugSelectivity 113
5.11 SmartInnovation 114
5.12 ElectronicHealth 115
5.13 DoctorandPatient 115
5.14 TheCompetentPatient 116
5.15 Conclusion 117
References 117
6 DrugDiscoveryStrategiesfortheGenerationofMultitarget
LigandsagainstNeglectedTropicalDiseases 135
AnnachiaraGandini,FedericaPrati,ElisaUliassi,andMariaL.Bolognesi
6.1 Introduction 135
6.2 DrugDiscoveryforNTDs:ThePast,thePresent,andthe
Future 136
6.3 SearchforNewAnti-TrypanosomatidMTDLHits:APhenotypic
Approach 138
6.4 SearchforNewAnti-TrypanosomatidMTDLHits:ATarget-Based
Approach 141
6.5 SearchforNewAnti-TrypanosomatidMTDLHits:ADrugTargeting
Approach 146
viii Contents
6.6 SearchforNewAnti-TrypanosomatidMTDLHits:ACombined
Target/TargetingApproach 149
6.7 Conclusions 151
References 152
7 DesigningApproachestoMultitargetDrugs 161
LucaCostantinoandDanielaBarlocco
7.1 Introduction 161
7.2 Target-BasedApproachesforMultitargetDrugDesign 163
7.2.1 DesigningApproachesforStructurallyRelatedTargets 163
7.2.1.1 Fragment-BasedApproach 163
7.2.2 DesigningApproachesforStructurallyUnrelatedTargets 166
7.2.2.1 Crystallography/SAR 166
7.2.2.2 MolecularDocking/PharmacophoreMatching 167
7.3 Ligand-BasedApproachesforMultitargetDrugDesign 170
7.3.1 DesigningApproachesforStructurallyRelatedTargets 170
7.3.1.1 Fragment-BasedApproach 170
7.3.1.2 MachineLearning 171
7.3.1.3 SARaroundaLead 173
7.3.1.4 Pharmacophore-BasedApproach 176
7.3.2 Designing-InApproachesforStructurallyUnrelatedTargets 180
7.3.2.1 Fragment-BasedApproach 180
7.3.2.2 Pharmacophore-BasedApproach 180
7.3.2.3 SARaroundaLead 181
7.3.2.4 MiningLiteratureData 183
7.4 DesigningApproachesBasedonPhenotypicAssays 186
7.5 Conclusions 189
References 191
8 TheLinkerApproach:DrugConjugates 207
DanielMerkandManfredSchubert-Zsilavecz
8.1 Introduction 207
8.1.1 TargetedDelivery 209
8.2 DrugConjugates 209
8.2.1 SmallMoleculeDrugConjugates 209
8.2.1.1 ChancesandChallenges 209
8.2.1.2 Examples 210
8.2.2 Antibody–DrugConjugates/Protein–DrugConjugates 217
8.2.2.1 ChancesandChallenges 218
8.2.2.2 Examples 219
8.2.3 Polymer–DrugConjugates 223
8.2.3.1 ChancesandChallenges 223
8.2.3.2 Examples 226
8.3 LinkerChemistry 229
8.3.1 DemandsonaLinkerorHowtoLinkDrugs 229
8.3.2 LinkerTypes 231
8.4 ConclusionandFuturePerspective 233
References 236
Contents ix
9 MergedMultipleLigands 247
HongmingChen,UdoBauer,andOlaEngkvist
9.1 Introduction 247
9.2 ComputationalMethodsUtilizedinDesigningMMLs 248
9.2.1 BioactivityDataSources 248
9.2.2 UtilizingKnownPolypharmacologytoIdentifyMMLs 248
9.2.3 ApplyingQSARModelstoIdentifyingandOptimizingMMLs 249
9.2.4 MMLsDevelopedBasedonFragments 250
9.2.5 UtilizingProteinCrystalStructuresinIdentifyingMMLs 250
9.3 ExamplesofMedicinalChemistryEffortsofDesigningMMLsinDrug
DiscoveryProjects 251
9.3.1 MMLsinOncology 251
9.3.2 MMLTargetingforNeurodegenerativeDisease 255
9.3.2.1 MMLsfortheTreatmentofAlzheimer’sDisease 256
9.3.2.2 MMLfortheTreatmentofParkinson’sDisease 257
9.3.3 MMLfortheTreatmentofDepression 261
9.3.4 MMLsfortheTreatmentofCardiovascularDiseases 262
9.3.5 MMLfortheTreatmentofDiabetesandRelatedMetabolic
Diseases 264
9.3.6 MMLfortheTreatmentofInflammationandPain 267
9.4 ConclusionsandFutureOutlook 269
References 269
10 PharmacophoreGenerationforMultipleLigands 275
NorbertHandler
10.1 Introduction 275
10.2 Ligand-BasedPharmacophoreModeling 276
10.3 Structure-BasedPharmacophoreModeling 278
10.4 Pharmacophore-BasedVirtualScreening 279
10.5 Pharmacophore-BasedDeNovoDesign 280
10.6 LimitationsforPharmacophoreModeling 282
10.7 PracticalStrategyforPharmacophore-BasedDiscoveryofMultiple
Ligands 283
10.8 LinkedFluoroquinolone–FlavonoidHybridsasPotentAntibiotics
againstDrug-ResistantMicroorganisms 285
10.9 N-Phenylquinazolin-4-AmineHybridsasDualInhibitorsofVEGFR-2
andHDAC 286
10.10 DualInhibitorsofPhospholipaseA2andHumanLeukotrieneA4
HydrolaseasAnti-InflammatoryDrugs 287
10.11 DualAntagonistsoftheBradykininB andB ReceptorsBasedona
1 2
PostulatedCommonPharmacophorefromExistingNon-Peptide
Antagonists 290
10.12 Dual-ActingPeptidomimeticswithOpioidAgonist–Neurokinin-1
AntagonistEffect 292
10.13 NovelDual-ActingCompoundsTargetingtheAdenosineA Receptor
2A
andAdenosineTransporterforNeuroprotection 292
10.14 AminobenzimidazolesasDual-ActingButyrylcholinesteraseInhibitors
andhCB RLigandstoCombatNeurodegenerativeDisorders 295
2