Fragment-Based Drug Discovery and X-Ray Crystallography PDF
Preview Fragment-Based Drug Discovery and X-Ray Crystallography
317 Topics in Current Chemistry Editorial Board: K.N. Houk C.A. Hunter M.J. Krische J.-M. Lehn l l l S.V. Ley M. Olivucci J. Thiem M. Venturi P. Vogel l l l l C.-H. Wong H. Wong H. Yamamoto l l Topics in Current Chemistry Recently Published and Forthcoming Volumes Fragment-BasedDrugDiscoveryandX-Ray FluorousChemistry Crystallography VolumeEditor:Istva´nT.Horva´th VolumeEditors:ThomasG.Davies, Vol.308,2012 MarkoHyvo¨nen MultiscaleMolecularMethodsinApplied Vol.317,2012 Chemistry VolumeEditors:BarbaraKirchner,JadranVrabec NovelSamplingApproachesinHigher Vol.307,2012 DimensionalNMR VolumeEditors:MartinBilleter, SolidStateNMR VladislavOrekhov VolumeEditor:JerryC.C.Chan Vol.316,2012 Vol.306,2012 AdvancedX-RayCrystallography PrionProteins VolumeEditor:KariRissanen VolumeEditor:Jo¨rgTatzelt Vol.315,2012 Vol.305,2011 Microfluidics:TechnologiesandApplications Pyrethroids:FromChrysanthemumtoModern VolumeEditor:BingchengLin IndustrialInsecticide Vol.304,2011 VolumeEditors:NoritadaMatsuo,TatsuyaMori Vol.314,2012 Photocatalysis VolumeEditor:CarloAlbertoBignozzi UnimolecularandSupramolecular Vol.303,2011 ElectronicsII VolumeEditor:RobertM.Metzger ComputationalMechanismsofAuandPt Vol.313,2012 CatalyzedReactions VolumeEditors:ElenaSoriano, UnimolecularandSupramolecular Jose´Marco-Contelles ElectronicsI Vol.302,2011 VolumeEditor:RobertM.Metzger Vol.312,2012 ReactivityTuninginOligosaccharideAssembly VolumeEditors:BertFraser-Reid, Bismuth-MediatedOrganicReactions J.Cristo´balLo´pez VolumeEditor:ThierryOllevier Vol.301,2011 Vol.311,2012 LuminescenceAppliedinSensorScience Peptide-BasedMaterials VolumeEditors:LucaProdi,MarcoMontalti, VolumeEditor:TimothyDeming NelsiZaccheroni Vol.310,2012 Vol.300,2011 AlkaloidSynthesis ChemistryofOpioids VolumeEditor:Hans-JoachimKno¨lker VolumeEditor:HiroshiNagase Vol.309,2012 Vol.299,2011 Fragment-Based Drug Discovery and X-Ray Crystallography Volume Editors: Thomas G. Davies (cid:1) Marko Hyvo¨nen With Contributions by E. Arnold (cid:1) J.D. Bauman (cid:1) P. Brough (cid:1) T.G. Davies (cid:1) H.L. Eaton (cid:1) D.A. Erlanson (cid:1) S. Greive (cid:1) M. Hennig (cid:1) W. Huber (cid:1) R.E. Hubbard (cid:1) M.Hyvo¨nen(cid:1)M.Marsh(cid:1)A.Massey(cid:1)D.Patel(cid:1)A.Ruf(cid:1)D.Rognan(cid:1) S.Roughley(cid:1)T.Sharpe(cid:1)A.W.Stamford(cid:1)C.Strickland(cid:1)I.J.Tickle(cid:1) E.Valkov (cid:1) J.H. Voigt (cid:1) Y.-S.Wang (cid:1) L.Wright(cid:1) D.F. Wyss(cid:1) Z.Zhu Editors Dr.ThomasG.Davies Dr.MarkoHyvo¨nen AstexPharmaceuticals DepartmentofBiochemistry 436CambridgeSciencePark UniversityofCambridge MiltonRoad 80TennisCourtRoad CambridgeCB40QA CambridgeCB21GA UK UK [email protected] [email protected] ISSN0340-1022 e-ISSN1436-5049 ISBN978-3-642-27539-5 e-ISBN978-3-642-27540-1 DOI10.1007/978-3-642-27540-1 SpringerHeidelbergDordrechtLondonNewYork LibraryofCongressControlNumber:2011945781 #Springer-VerlagBerlinHeidelberg2012 Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthematerialis concerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broadcasting, reproductiononmicrofilmorinanyotherway,andstorageindatabanks.Duplicationofthispublication orpartsthereofispermittedonlyundertheprovisionsoftheGermanCopyrightLawofSeptember9, 1965,initscurrentversion,andpermissionforusemustalwaysbeobtainedfromSpringer.Violations areliabletoprosecutionundertheGermanCopyrightLaw. 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Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) Volume Editors Dr.ThomasG.Davies Dr.MarkoHyvo¨nen AstexPharmaceuticals DepartmentofBiochemistry 436CambridgeSciencePark UniversityofCambridge MiltonRoad 80TennisCourtRoad CambridgeCB40QA CambridgeCB21GA UK UK [email protected] [email protected] Editorial Board Prof.Dr.KendallN.Houk Prof.Dr.StevenV.Ley UniversityofCalifornia UniversityChemicalLaboratory DepartmentofChemistryandBiochemistry LensfieldRoad 405HilgardAvenue CambridgeCB21EW LosAngeles,CA90024-1589,USA GreatBritain [email protected] [email protected] Prof.Dr.ChristopherA.Hunter Prof.Dr.MassimoOlivucci DepartmentofChemistry Universita`diSiena UniversityofSheffield DipartimentodiChimica SheffieldS37HF,UnitedKingdom ViaADeGasperi2 c.hunter@sheffield.ac.uk 53100Siena,Italy [email protected] Prof.MichaelJ.Krische Prof.Dr.JoachimThiem UniversityofTexasatAustin Institutfu¨rOrganischeChemie Chemistry&Biochemistry Department Universita¨tHamburg 1UniversityStationA5300 Martin-Luther-King-Platz6 AustinTX,78712-0165,USA 20146Hamburg,Germany [email protected] [email protected] Prof.Dr.Jean-MarieLehn Prof.Dr.MargheritaVenturi ISIS DipartimentodiChimica 8,alle´eGaspardMonge Universita`diBologna BP70028 viaSelmi2 67083StrasbourgCedex,France 40126Bologna,Italy [email protected] [email protected] vi EditorialBoard Prof.Dr.PierreVogel Prof.Dr.HenryWong LaboratoryofGlycochemistry TheChineseUniversityofHongKong andAsymmetricSynthesis UniversityScienceCentre EPFL–Ecolepolytechniquefe´derale DepartmentofChemistry deLausanne Shatin,NewTerritories EPFLSBISICLGSA [email protected] BCH5307(Bat.BCH) 1015Lausanne,Switzerland Prof.Dr.HisashiYamamoto pierre.vogel@epfl.ch ArthurHollyComptonDistinguished Prof.Dr.Chi-HueyWong Professor DepartmentofChemistry Professor of Chemistry, Scripps Research TheUniversityofChicago Institute 5735SouthEllisAvenue PresidentofAcademiaSinica Chicago,IL60637 AcademiaSinica 773-702-5059 128AcademiaRoad USA Section2,Nankang [email protected] Taipei115 Taiwan [email protected] Topics in Current Chemistry Also Available Electronically Topics in Current Chemistry is included in Springer’s eBook package Chemistry andMaterialsScience.Ifalibrarydoesnotoptforthewholepackagethebookseries may be bought on a subscription basis. 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InreferencesTopicsinCurrentChemistryisabbreviatedTop CurrChemandis citedasajournal. ImpactFactor2010:2.067;Section“Chemistry,Multidisciplinary”:Rank44of144 Preface Thefragment-basedapproachhasemergedinthelastdecadeasahighlypromising component of modern drug discovery. Despite its relatively short history, it has beenthesubjectofmanyresearcharticles,reviewsandbooks,andisresponsiblefor several compounds currently in clinical development. Its contribution is increas- ingly recognized by the medicinal chemistry community, and it now forms an importantpartofdrugdiscoveryeffortswithinthepharmaceuticalindustry. Despite the exponential growth of interest in this field, fragment-based drug discovery(FBDD)representsasignificantparadigmshiftfordrugdiscoverers,both philosophically, and in terms of methodology and work-flow. In particular, it has required a shift away from relatively potent, drug-like hits, readily identified by enzymatic high-throughput assays, to the more challenging detection of very weakly (but efficiently) bindingcompounds. As such, the development andappli- cationofrobustandsensitivebiophysicaltechniquestodetectandcharacterisethe bindingofsimple, lowmolecularcompounds has beenakeypartofenablingthis approach.X-raycrystallographywasoneoftheearliesttechniquesdemonstratedto be capable of detecting the binding of fragments, and its additional ability to provide precise three-dimensional detail on their binding modes, and hence guide theirsubsequentelaborationhasledtoitplayingacentralroleinthisapproach. In this volume we bring together chapters by a number of practitioners in the field,drawnfromboththepharmaceuticalindustryandacademia.Ouraimhasbeen to highlight the important roles that X-ray crystallography plays in the fragment- approach: as a sensitive technique for primary screening, its use in combination withotherbiophysicaltechniquestoallowrobusthitvalidation,anditsimportance inprovidingstructuralinformationtoguideprogressionfromhittoclinicalcandi- date. Inthefirstchapter,ErlansonfromCarmotTherapeuticsprovidesanintroduction totheFBDDfieldasawhole,highlightingsomeoftheadvantagesoffragmentsand their means of detection, and giving examples of fragment-derived compounds whichhavealreadyreachedtheclinic.DaviesandTicklefromAstexTherapeutics then provide a review oftheuse ofX-ray crystallography for fragment screening, ix x Preface anddescribesomeofthecomputationaldevelopmentsdevelopedatAstexthathave allowed the rapid generation of protein-ligand structural data required for this approach. In chapter 3, Roughley and colleagues from Vernalis present the first of a number of personal case studies of FBDD – in this case, the application of the fragment-approach to the development of Hsp90 inhibitors, with emphasis on the role of in silico screening, and its interplay with experimental structural informa- tion. This is followed by a chapter from Wyss et al (Merck), who describe their work on the fragment-based development of BACE inhibitors and how comple- mentaryinformationfrombothNMRandX-raycrystallographywerecombinedto successfully prosecute a drug discovery campaign against this important target. Continuingonthethemeofcombiningbiophysicaltechniques,Hennigandcollea- gues then describe the approach to FBDD taken at Roche, and in particular how Surface Plasmon Resonance and structural information are used together in an integratedapproach. Fragment-basedapproachesareincreasinglybeingappliedtochallengingthera- peutic targets, and in particular those for which conventional drug discovery methods have failed. In chapter 6, Valkov and colleagues (University of Cambridge)provideareviewofsmallmoleculeinhibitionofprotein-proteininter- actions,andtheapplicationoffragment-basedmethodsagainstthisclassoftarget. Bauman et al (Rutgers) then describe the use of X-ray crystallographic fragment screeningtoidentifynovelhitsagainstHIVtargets,andhighlightthegrowingtrend foracademic-basedFBDD.Indeed,thecloseassociationofbiophysicalandstruc- tural techniques, combined with the manageable size of screening libraries make fragment-basedmethodsincreasinglyappealingandaccessibletoacademiclabora- toriesinadditiontothoseinthepharmaceuticalindustry. In the concluding chapter, and in a departure from the predominantly experi- mental methods discussed above, Rognan (University of Strasbourg) provides a computational perspective on the fragment-based approach, and discusses the application and development of insilico approaches whichare increasinglybeing appliedinthisarea. Wehopethisbookwillprovideausefulintroductiontosomeofthekeyconcepts and techniques in fragment-based drug discovery, highlighting the diverse set of targets it is applied to, as well as emphasizing the importance of structural infor- mation in this field. The application of X-ray crystallography to structure-based drugdiscoveryisnowamaturediscipline,butonewhosepotentialhassometimes beenunder-exploited.Indrivingvariousaspectsofthefragment-basedapproach,it clearlyplaysacentralrole. Cambridge,January2012 ThomasDavies MarkoHyvo¨nen
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