Chemical library design PDF
Preview Chemical library design
Chemical Library Design Editedby Joe Zhongxiang Zhou DepartmentofPharmacology,UniversityofCalifornia,SanDiego,CA,USA Editor JoeZhongxiangZhou DepartmentofPharmacology UniversityofCalifornia LaJolla,CA92093,USA [email protected] ISSN1064-3745 e-ISSN1940-6029 ISBN978-1-60761-930-7 e-ISBN978-1-60761-931-4 DOI10.1007/978-1-60761-931-4 SpringerNewYorkDordrechtHeidelbergLondon LibraryofCongressControlNumber:2010937983 ©SpringerScience+BusinessMedia,LLC2011 Allrightsreserved.Thisworkmaynotbetranslatedorcopiedinwholeorinpartwithoutthewrittenpermissionof thepublisher(HumanaPress,c/oSpringerScience+BusinessMedia,LLC,233SpringStreet,NewYork,NY10013, USA),exceptforbriefexcerptsinconnectionwithreviewsorscholarlyanalysis.Useinconnectionwithanyformof informationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology nowknownorhereafterdevelopedisforbidden. Theuseinthispublicationoftradenames,trademarks,servicemarks,andsimilarterms,eveniftheyarenotidentified assuch,isnottobetakenasanexpressionofopinionastowhetherornottheyaresubjecttoproprietaryrights. Printedonacid-freepaper HumanaPressispartofSpringerScience+BusinessMedia(www.springer.com) Preface Over the last two decades we have seen a dramatic change in the drug discovery process brought about by chemical library technologies and high-throughput screening, along with other equally remarkable advances in biomedical research. Though still evolving, chemical library technologies have become an integral part of the core drug discovery technologies. This volume primarily focuses on the design aspects of the chemical library technologies.Librarydesignisaprocessofselectingusefulcompoundsfromapotentially very large pool of synthesizable candidates. For drug discovery, the selected compounds have to be biologically relevant. Given the enormous number of compounds accessible to the contemporary synthesis and purification technologies, powerful tools are indis- pensible for uncovering those few useful ones. This book includes chapters on historical overviews,state-of-the-artmethodologies,practicalsoftwaretools,andsuccessfulapplica- tionsofchemicallibrarydesignwrittenbythebestexpertpractitioners. Thebookisdividedintofivesection.SectionIcoversgeneraltopics.Chapter1high- lights the key events in the history of high-throughput chemistry and offers a historical perspective on the design of screening, targeted, and optimization libraries. Chapter 2 is ashortintroductiontothebasicsofchemoinformaticsnecessaryforlibrarydesign.Chap- ter3describesapracticalalgorithmformultiobjectivelibrarydesign.Chapter4discusses a scalable approach to designing lead generation libraries that emphasize both diversity and representativeness along with other objectives. Chapter 5 explains how Free–Wilson selectivity analysis can be used to aid combinatorial library design. Chapter 6 shows how predictive QSAR and shape pharmacophore models can be successfully applied to tar- geted library design. Chapter 7 describes a combinatorial library design method based on reagent pharmacophore fingerprints to achieve optimal coverage of pharmacophoric featuresforagivenscaffold. ThreechaptersinSectionIIfocusonthemethodsandapplicationsofstructure-based librarydesign.Chapter8reviewsthedockingmethodsforstructure-basedlibrarydesign. Chapters 9 and 10 contain two detailed protocols illustrating how to apply structure- basedlibrarydesigntothesuccessfuloptimizationofleadmattersintherealdrugdiscov- eryprojects. Section III consists of three chapters on fragment-based library design. Chapter 11 describesthekeyfactorsthatdefineagoodfragmentlibraryforsuccessfulfragment-based drug discovery. It also provides a summary view of the fragment libraries published so far by various pharmaceutical companies. Chapter 12 shows how a fragment library is used in fragment-based drug design. Chapter 13 introduces a new chemical structure mining methodthatsearchesintoahugevirtuallibraryofcombinatorialorigin.Themethoduses fragmental(orpartial)mappingsbetweenthequerystructureandthetargetmoleculesin itsinitialsearchalgorithms. Chapter14inSectionIVdescribesaworkflowfordesigningakinasetargetedlibrary. It illustrates how to assemble a lead generation library for a target family using known ligand–targetfamilyinteractiondatafromvarioussources. Section V contains four chapters on library design tools. PGVL Hub described in Chapter 15 is an integrated desktop tool for molecular design including library design. It streamlines the design workflow from product structure formation to property v vi Preface calculations,tofiltering,tointerfaceswithothersoftwaretools,andtolibraryproduction management. An application of PGVL Hub to the optimization of human CHK1 kinase inhibitors is presented in Chapter 16. Chapter 17 is a detailed protocol on how to use librarydesigntoolGLAREtoperformproduct-orienteddesignofcombinatoriallibraries. Finally,Chapter 18isadetailedprotocolonhowtousethelibrarydesigntoolCLEVER toperformlibrarydesignandvisualization. JoeZhongxiangZhou Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix SECTION I GENERAL TOPICS 1. HistoricalOverviewofChemicalLibraryDesign . . . . . . . . . . . . . . . . . 3 RolandE.Dolle 2. ChemoinformaticsandLibraryDesign . . . . . . . . . . . . . . . . . . . . . . 27 JoeZhongxiangZhou 3. MolecularLibraryDesignUsingMulti-ObjectiveOptimizationMethods . . . . 53 ChristosA.NicolaouandChristosC.Kannas 4. AScalableApproachtoCombinatorialLibraryDesign . . . . . . . . . . . . . . 71 PuneetSharma,SrinivasaSalapaka,andCarolynBeck 5. Application of Free–Wilson Selectivity Analysis for Combinatorial LibraryDesign . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 SimoneSciabola,RobertV.Stanton,TheresaL.Johnson,andHualinXi 6. ApplicationofQSARandShapePharmacophoreModelingApproaches forTargetedChemicalLibraryDesign . . . . . . . . . . . . . . . . . . . . . . 111 JerryO.Ebalunode,WeifanZheng,andAlexanderTropsha 7. CombinatorialLibraryDesignfromReagentPharmacophoreFingerprints . . . . 135 HongmingChen,OlaEngkvist,andNiklasBlomberg SECTION II STRUCTURE-BASEDLIBRARY DESIGN 8. DockingMethodsforStructure-BasedLibraryDesign . . . . . . . . . . . . . . 155 ClaudioN.CavasottoandSharangdharS.Phatak 9. Structure-Based Library Design in Efficient Discovery ofNovelInhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 ShunqiYanandRobertSelliah 10. Structure-BasedandProperty-CompliantLibraryDesign of11β-HSD1AdamantylAmideInhibitors . . . . . . . . . . . . . . . . . . . . 191 GenevieveD.Paderes,KlausDress,BuwenHuang,JeffElleraas, PaulA.Rejto,andTomPauly SECTION III FRAGMENT-BASEDLIBRARY DESIGN 11. Design of Screening Collections for Successful Fragment-Based LeadDiscovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 JamesNaandQiyueHu vii viii Contents 12. Fragment-BasedDrugDesign. . . . . . . . . . . . . . . . . . . . . . . . . . . 241 EricFeyfant,JasonB.Cross,KevinParis,andDésiréeH.H.Tsao 13. LEAP into the Pfizer Global Virtual Library (PGVL) Space: Creation ofReadilySynthesizableDesignIdeasAutomatically . . . . . . . . . . . . . . . 253 QiyueHu,ZhengweiPeng,JaroslavKostrowicki,andAtsuoKuki SECTION IV LIBRARY DESIGN FOR KINASE FAMILY 14. TheDesign,Annotation,andApplicationofaKinase-TargetedLibrary . . . . . 279 HualinXiandElizabethA.Lunney SECTION V LIBRARY DESIGN TOOLS 15. PGVL Hub: An Integrated Desktop Tool for Medicinal Chemists to Streamline Design and Synthesis of Chemical Libraries andSingletonCompounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 ZhengweiPeng,BoYang,SarathyMattaparti,ThomShulok, ThomasThacher,JamesKong,JaroslavKostrowicki,QiyueHu, JamesNa,JoeZhongxiangZhou,DavidKlatte,BoChao,ShogoIto, JohnClark,NunzioSciammetta,BobConer,ChrisWaller, andAtsuoKuki 16. Design of Targeted Libraries Against the Human Chk1 Kinase UsingPGVLHub . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 ZhengweiPengandQiyueHu 17. GLARE:AToolforProduct-OrientedDesignofCombinatorialLibraries . . . . 337 Jean-FrançoisTruchon 18. CLEVER:AGeneralDesignToolforCombinatorialLibraries . . . . . . . . . . 347 TzeHauLam,PaulH.Bernardo,ChristinaL.L.Chai, andJooChuanTong SubjectIndex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 Contributors CAROLYN BECK • Department of Industrial and Enterprise Systems Engineering, UniversityofIllinoisatUrbanaChampaign,Urbana,IL,USA PAUL H. BERNARDO • Institute of Chemical and Engineering Sciences, Singapore, Singapore NIKLAS BLOMBERG • DECS GCS Computational Chemistry, AstraZeneca R&D Mölndal,Mölndal,Sweden CLAUDIO N. CAVASOTTO • School of Biomedical Informatics, The University of Texas HealthScienceCenteratHouston,Houston,TX,USA CHRISTINA L.L. CHAI • Institute of Chemical and Engineering Sciences, Singapore, Singapore BO CHAO • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA HONGMING CHEN • DECS GCS Computational Chemistry, AstraZeneca R&D Mölndal,Mölndal,Sweden JOHN CLARK • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA BOB CONER • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA JASON B.CROSS • Cubistpharmaceuticals,Inc.,Lexington,MA,USA ROLAND E.DOLLE • DepartmentofChemistry,AdolorCorporation,Exton,PA,USA KLAUS DRESS • Oncology Medicinal Chemistry, La Jolla Laboratories, Pfizer Inc., San Diego,CA,USA JERRY O. EBALUNODE • Department of Pharmaceutical Sciences, BRITE Institute, NorthCarolinaCenterUniversity,Durham,NC,USA JEFF ELLERAAS • Oncology Medicinal Chemistry, La Jolla Laboratories, Pfizer Inc., San Diego,CA,USA OLA ENGKVIST • DECS GCS Computational Chemistry, AstraZeneca R&D Mölndal, Mölndal,Sweden ERIC FEYFANT • PfizerGlobalR&D,Cambridge,MA,USA QIYUE HU • Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA,USA BUWEN HUANG • Oncology Medicinal Chemistry, La Jolla Laboratories, Pfizer Inc., San Diego,CA,USA SHOGO ITO • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA THERESA L.JOHNSON • PfizerResearchTechnologyCenter,Cambridge,MA,USA CHRISTOSC.KANNAS • DepartmentofComputerScience,UniversityOfCyprus,Nicosia, Cyprus;NoesisChemoinformatics,Nicosia,Cyprus DAVID KLATTE • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA JAMES KONG • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA JAROSLAV KOSTROWICKI • Pfizer Global Research and Development, La Jolla Laboratories,SanDiego,CA,USA ATSUOKUKI • PfizerGlobalResearchandDevelopment,LaJollaLaboratories,SanDiego, CA,USA TZE HAU LAM • Data Mining Department, Institute for Infocomm Research,Singapore, Singapore ix x Contributors ELIZABETH A.LUNNEY • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA SARATHY MATTAPARTI • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA JAMES NA • Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA,USA CHRISTOS A.NICOLAOU • NoesisChemoinformatics,Nicosia,Cyprus GENEVIEVE D. PADERES • Cancer Crystallography & Computational Chemistry, La JollaLaboratories,PfizerInc.,SanDiego,CA,USA KEVIN PARIS • PfizerGlobalR&D,Cambridge,MA,USA TOM PAULY • Oncology Medicinal Chemistry, La Jolla Laboratories, Pfizer Inc., San Diego,CA,USA ZHENGWEI PENG • Pfizer Global Research and Development, La Jolla Laboratories, San Diego,CA,USA SHARANGDHAR S. PHATAK • School of Biomedical Informatics, The University of Texas HealthScienceCenteratHouston,Houston,TX,USA PAUL A.REJTO • Oncology,LaJollaLaboratories,PfizerInc.,SanDiego,CA,USA SRINIVASA SALAPAKA • Department of Mechanical Science and Engineering, University ofIllinoisatUrbanaChampaign,Urbana,IL,USA SIMONE SCIABOLA • PfizerResearchTechnologyCenter,Cambridge,MA,USA NUNZIO SCIAMMETTA • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA ROBERT SELLIAH • DrugDesignConsulting,Irvine,CA,USA PUNEET SHARMA • Integrated Data Systems Department, Siemens Corporate Research, Princeton,NJ,USA THOM SHULOK • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA ROBERT V.STANTON • PfizerResearchTechnologyCenter,Cambridge,MA,USA THOMAS THACHER • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA JOO CHUAN TONG • Data Mining Department, Institute for Infocomm Research, Singapore, Singapore; Department of Biochemistry, Yong Loo School of Medicine, NationalUniversityofSingapore,Singapore,Singapore ALEXANDER TROPSHA • Laboratory for Molecular Modeling and Carolina Center for Exploratory Cheminformatics Research, School of Pharmacy, University of North CarolinaatChapelHill,ChapelHill,NC,USA JEAN-FRANÇOIS TRUCHON • Chemical Modeling and Informatics, Merck Frosst Canada,Kirkland,QC,Canada DÉSIRÉE H.H.TSAO • PfizerGlobalR&D,Cambridge,MA,USA CHRIS WALLER • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA HUALIN XI • PfizerResearchTechnologyCenter,Cambridge,MA,USA SHUNQI YAN • DrugDesignConsulting,Irvine,CA,USA BO YANG • PGRD-LaJolla,PfizerInc.,SanDiego,CA,USA WEIFAN ZHENG • Department of Pharmaceutical Sciences, BRITE Institute, North CarolinaCenterUniversity,Durham,NC,USA JOE ZHONGXIANG ZHOU • PGRD-La Jolla, Pfizer Inc., San Diego, CA, USA; DepartmentofPharmacology,UniversityofCalifornia,SanDiego,CA,USA Section I General Topics Chapter 1 Historical Overview of Chemical Library Design Roland E. Dolle Abstract High-throughput chemistry (HTC) is approaching its 20-year anniversary. Since 1992, some 5,000 chemical libraries, prepared for the purpose of biological intestigation and drug discovery, have been published in the scientific literature. This review highlights the key events in the history of HTC with emphasisonlibrarydesign.Ahistoricalperspectiveonthedesignofscreening,targeted,andoptimiza- tionlibrariesandtheirapplicationispresented.Designstrategiespioneeredinthe1990sremainviablein thetwenty-firstcentury. Key words: High-throughput chemistry, chemical library, random library, targeted library, optimizationlibrary,librarydesign,biologicalactivity,drugdiscovery. 1. Milestonesin High-Throughput Chemistry High-throughput chemistry (HTC) is a widely used technology for accelerating the synthesis of chemical compounds, in partic- ular the synthesis of biologically active compounds. HTC orig- inated in the early 1990s. Its development and application was largely driven by the pharmaceutical industry. In the years lead- ing up to the introduction of HTC, the pharmaceutical industry had been transformed by advances in molecular biology. Rou- tine cloning and expression of molecular targets enabled medic- inal chemists to optimize the potency of chemical leads directly against an enzyme or receptor prior to in vivo testing. Brim- mingwithmoleculartargetsandnascenthigh-throughputscreen- ing technology, there was a demand to access large compound collections to discover new drug leads. Vintage industrial com- pound collections generated over many decades amounted to J.Z.Zhou(ed.),ChemicalLibraryDesign,MethodsinMolecularBiology685, DOI10.1007/978-1-60761-931-4_1,©SpringerScience+BusinessMedia,LLC2011 3
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