Bioisosteres in medicinal chemistry

258 Pages·2012·13.396 MB·English

by  Nathan Brown

54 MethodsandPrinciplesinMedicinalChemistry
B Edited by Nathan Brown
r
o
W
rittenwiththepracticingmedicinalchemistinmind,thisisthefirst w
modernhandbooktosystematicallyaddressthetopicofbioisosterism. n
Assuch,itprovidesareadyreferenceontheprinciplesandmethodsof (
E Bioisosteres
bioisostericreplacementasakeytoolinpreclinicaldrugdevelopment.
d
Thefirstpartprovidesanoverviewofbioisosterism,classical .
)
bioisosteresandtypicalmolecularinteractionsthatneedtobeconsid-
ered,whilethesecondpartdescribesanumberofmoleculardatabasesas
in Medicinal Chemistry
sourcesofbioisostericidentificationandrationalization.Thethirdpart
coversthefourkeymethodologiesforbioisostereidentificationandre-
placement:physicochemicalproperties,topology,shape,andoverlaysof
protein-ligandcrystalstructures.Inthefinalpart,severalreal-worldexam-
plesofbioisosterismindrugdiscoveryprojectsarediscussed.
Withitsdetaileddescriptionsofdatabases,methodsandreal-lifecase
studies,thisistailor-madeforbusyindustrialresearcherswithlittletime
forreading,whileremainingeasilyaccessibletonovicedrugdevelopers
duetoitssystematicstructureandintroductorysection.
NathanBrownistheHeadoftheInSilicoMedicinalChemistry
groupintheCancerResearchUKCancerTherapeuticsUnitat
theInstituteofCancerResearchinLondon(UK).AttheICR,
Dr.Brownandhisgroupsupporttheentiredrugdiscoveryport- Volume 54
foliotogetherwithdevelopingnewcomputationalmethodologies i B
n
toenhancethedrugdesignwork. i
o
NathanBrownconductedhisdoctoralresearchinSheffield M
i SeriesEditors:
withProfessorPeterWillettfocusingonevolutionaryalgorithms s
e
andgraphtheoryappliedtochallengesinchemoinformatics.After o
d R.Mannhold,
atwo-yearMarieCuriefellowshipinAmsterdamincollaboration s
withProfessorJohannGasteigerinErlangen,hejoinedthe ic te H.Kubinyi,
i
NovartisInstitutesforBioMedicalResearchinBaselforathree- n r
e
yearPresidentialfellowshipinBaselworkingwithProfessorsPeter a G.Folkers
s
WillettandKarl-HeinzAltmann. l
Hisworkhasledtothepioneeringworkonmulitobjectivede C
novodesigninadditiontoavarietyofdiscoveriesandmethod h
developmentinbioisostericidentificationandreplacement, e
scaffoldhopping,moleculardescriptorsandstatisticalmodeling. m
Nathancontinuestopursuehisresearchinallaspectsofinsilico i
medicinalchemistry. s
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www.wiley-vch.de

Edited by
Nathan Brown
Bioisosteres in Medicinal
Chemistry
Methods and Principles in Medicinal Chemistry
EditedbyR.Mannhold,H.Kubinyi,G.Folkers
EditorialBoard
H.Buschmann,H.Timmerman,H.van deWaterbeemd,T.Wieland
Previous Volumes of this Series:
Gohlke,Holger(Ed.) Sotriffer,Christoph(Ed.)
Protein-LigandInteractions VirtualScreening
2012 Principles,Challenges,andPractical
ISBN:978-3-527-32966-3 Guidelines
Vol.53
2011
Kappe,C.Oliver/Stadler,Alexander/Dallinger,Doris ISBN:978-3-527-32636-5
MicrowavesinOrganic Vol.48
andMedicinalChemistry
Rautio,Jarkko(Ed.)
Second, CompletelyRevised
ProdrugsandTargetedDelivery
andEnlargedEdition
TowardsBetterADMEProperties
2012
2011
ISBN:978-3-527-33185-7
ISBN:978-3-527-32603-7
Vol.52
Vol.47
Smith,DennisA./Allerton,Charlotte/
Kalgutkar,AmitS./vandeWaterbeemd, Smit,MartineJ./Lira,SergioA./
Han/Walker,DonK. Leurs,Rob(Eds.)
PharmacokineticsandMetabolism ChemokineReceptorsasDrugTargets
inDrugDesign 2011
Third,RevisedandUpdatedEdition ISBN:978-3-527-32118-6
Vol.46
2012
ISBN:978-3-527-32954-0
Ghosh,ArunK.(Ed.)
Vol.51
AsparticAcidProteasesas
DeClercq,Erik(Ed.) TherapeuticTargets
AntiviralDrugStrategies
2010
2011 ISBN:978-3-527-31811-7
ISBN:978-3-527-32696-9 Vol.45
Vol.50
Ecker,GerhardF./Chiba,Peter(Eds.)
Klebl,Bert/Müller,Gerhard/Hamacher,
TransportersasDrugCarriers
Michael(Eds.)
ProteinKinasesasDrugTargets Structure,Function,Substrates
2011 2009
ISBN:978-3-527-31790-5 ISBN:978-3-527-31661-8
Vol.49 Vol.44
Edited by Nathan Brown
Bioisosteres in Medicinal Chemistry
SeriesEditors AllbookspublishedbyWiley-VCHarecarefully
produced.Nevertheless,authors,editors,andpub-
Prof.Dr.RaimundMannhold lisherdonotwarranttheinformationcontainedin
MolecularDrugResearchGroup thesebooks,includingthisbook,tobefreeoferrors.
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Prof.Dr.HugoKubinyi Acataloguerecordforthisbookisavailablefromthe
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CollegiumHelveticum bibliographicdataareavailableontheInternetat
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reproducedinanyform–byphotoprinting,micro-
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V
Contents
List of Contributors XI
Preface XV
A Personal Foreword XVII
PartOne Principles 1
1 BioisosterisminMedicinalChemistry 3
NathanBrown
1.1 Introduction 3
1.2 Isosterism 3
1.3 Bioisosterism 6
1.4 BioisosterisminLeadOptimization 9
1.4.1 CommonReplacementsinMedicinalChemistry 9
1.4.2 Structure-BasedDrugDesign 9
1.4.3 MultiobjectiveOptimization 12
1.5 Conclusions 13
References 14
2 ClassicalBioisosteres 15
CaterinaBarillariandNathanBrown
2.1 Introduction 15
2.2 HistoricalBackground 15
2.3 ClassicalBioisosteres 17
2.3.1 MonovalentAtomsandGroups 17
2.3.2 BivalentAtomsandGroups 17
2.3.3 TrivalentAtomsandGroups 18
2.3.4 TetravalentAtoms 19
2.3.5 RingEquivalents 19
2.4 NonclassicalBioisosteres 20
2.4.1 CarbonylGroup 20
2.4.2 CarboxylicAcid 21
2.4.3 HydroxylGroup 22
2.4.4 Catechol 22
VI Contents
2.4.5 Halogens 23
2.4.6 AmideandEsters 24
2.4.7 Thiourea 25
2.4.8 Pyridine 26
2.4.9 CyclicVersusNoncyclicSystems 27
2.5 Summary 27
References 27
3 ConsequencesofBioisostericReplacement 31
DennisA.SmithandDavidS.Millan
3.1 Introduction 31
3.2 BioisostericGroupingstoImprovePermeability 32
3.3 BioisostericGroupingstoLowerIntrinsicClearance 40
3.4 BioisostericGroupingstoImproveTargetPotency 43
3.5 ConclusionsandFuturePerspectives 47
References 49
PartTwo Data 53
4 BIOSTER:ADatabaseofBioisosteresandBioanalogues 55
IstvánUjváryandJulianHayward
4.1 Introduction 55
4.2 HistoricalOverviewandtheDevelopmentofBIOSTER 56
4.2.1 RepresentationofChemicalTransformationsforReaction
Databases 56
4.2.2 TheConceptof‘‘BiostericTransformation’’ 57
4.2.3 OtherAnalogueand BioisostereDatabases 58
4.3 DescriptionofBIOSTERDatabase 59
4.3.1 CoverageandSelectionCriteria 59
4.3.2 Sources 59
4.3.3 DescriptionoftheLayoutofDatabaseRecords 60
4.3.3.1 IDCode 60
4.3.3.2 BiostericTransformation 60
4.3.3.3 Citation(s) 62
4.3.3.4 Activity 63
4.3.3.5 Fragments 63
4.3.3.6 ComponentMoleculesandFragments 64
4.4 Examples 64
4.4.1 BenzodioxoleBioisosteres 65
4.4.2 PhenolBioisosteres 66
4.4.3 Ketoamides 66
4.5 Applications 69
4.6 Summary 70
4.7 Appendix 70
References 71
Contents VII
5 MiningtheCambridgeStructuralDatabaseforBioisosteres 75
ColinR.Groom,TjelvarS.G.Olsson,JohnW.Liebeschuetz,
DavidA.Bardwell,IanJ.Bruno,andFrankH.Allen
5.1 Introduction 75
5.2 TheCambridgeStructuralDatabase 76
5.3 TheCambridgeStructuralDatabaseSystem 78
5.3.1 ConQuest 78
5.3.2 Mercury 78
5.3.3 WebCSD 79
5.3.4 Knowledge-BasedLibrariesDerivedfromtheCSD 80
5.4 TheRelevanceoftheCSDtoDrugDiscovery 83
5.5 AssessingBioisosteres:ConformationalAspects 84
5.6 AssessingBioisosteres:NonbondedInteractions 86
5.7 FindingBioisosteresintheCSD:ScaffoldHoppingand
FragmentLinking 91
5.7.1 ScaffoldHopping 91
5.7.2 FragmentLinking 92
5.8 ACaseStudy:Bioisosterismof1H-TetrazoleandCarboxylic
AcidGroups 94
5.8.1 ConformationalMimicry 94
5.8.2 IntermolecularInteractions 94
5.9 Conclusions 97
References 98
6 MiningforContext-SensitiveBioisostericReplacements
inLargeChemicalDatabases 103
GeorgePapadatos,MichaelJ .Bodkin,ValerieJ.Gillet,
andPeterWillett
6.1 Introduction 103
6.2 Definitions 104
6.3 Background 105
6.4 MaterialsandMethods 109
6.4.1 HumanMicrosomalMetabolicStability 109
6.4.2 DataPreprocessing 109
6.4.3 GenerationofMatchedMolecularPairs 110
6.4.4 ContextDescriptors 111
6.4.4.1 WholeMoleculeDescriptors 111
6.4.4.2 LocalEnvironmentDescriptors 112
6.4.5 BinningofDPValues 112
6.4.6 ChartsandStatistics 112
6.5 ResultsandDiscussion 113
6.5.1 GeneralConsiderations 123
6.6 Conclusions 124
References 125
VIII Contents
PartThree Methods 129
7 PhysicochemicalProperties 131
PeterErtl
7.1 Introduction 131
7.2 MethodstoIdentifyBioisostericAnalogues 132
7.3 DescriptorstoCharacterizePropertiesofSubstituents
andSpacers 132
7.4 ClassicalMethodsforNavigationintheSubstituent
Space 135
7.5 ToolstoIdentifyBioisostericGroupsBasedonSimilarity
inTheirProperties 136
7.6 Conclusions 138
References 138
8 MolecularTopology 141
NathanBrown
8.1 Introduction 141
8.2 ControlledFuzziness 141
8.3 GraphTheory 142
8.4 DataMining 144
8.4.1 GraphMatching 144
8.4.2 FragmentationMethods 145
8.5 TopologicalPharmacophores 146
8.6 ReducedGraphs 149
8.7 Summary 151
References 152
9 MolecularShape 155
PedroJ.BallesterandNathanBrown
9.1 Methods 156
9.1.1 Superposition-BasedShapeSimilarityMethods 156
9.1.2 Superposition-FreeShapeSimilarityMethods 158
9.1.3 ChoosingaShapeSimilarityTechniqueforaParticular
Project 160
9.2 Applications 161
9.3 FutureProspects 164
References 165
10 ProteinStructure 167
JamesE.J.Mills
10.1 Introduction 167
10.2 DatabaseofLigand–ProteinComplexes 168
10.2.1 ExtractionofLigands 168
10.2.2 AssessmentofLigandandProteinCriteria 169