Drug Design: Structure- and Ligand-Based Approaches PDF
Preview Drug Design: Structure- and Ligand-Based Approaches
DRUG DESIGN: STRUCTURE- AND LIGAND-BASED APPROACHES Structure-baseddrugdesign(SBDD)andligand-baseddrugdesign(LBDD)areactiveareas ofresearchinboththeacademicandcommercialrealms.Thisbookprovidesacurrentsnap- shot of the field of computer-aided drug design and associated experimental approaches. Topics covered include x-ray crystallography, nuclear magnetic resonance, fragment-based drug design, free-energy methods, docking and scoring, linear-scaling quantum calcula- tions, quantitative structure/activity relationship, pharmacophore methods, computational absorption/distribution/metabolism/excretion-toxicity, and drug discovery case studies. Authorsfromacademicandcommercialinstitutionsallovertheworldhavecontributedto thisbook,whichisillustratedwithmorethan200images.ThisbookcoversSBDDandLBDD, anditprovidesthemostup-to-dateinformationonawiderangeoftopicsforthepracticing computationalchemist,medicinalchemist,orstructuralbiologist. KennethM.Merz,Jr.,receivedhisPhDinorganicchemistryattheUniversityofTexasatAustin andcompletedpostdoctoralresearchatCornellUniversityandtheUniversityofCalifornia, SanFrancisco.HeisamemberoftheQuantumTheoryProjectandProfessorofChemistryat theUniversityofFlorida,Gainesville. DagmarRingereceivedherPhDinbiochemistryatBostonUniversity.SheisProfessorofBio- chemistryandChemistryintheRosenstielBasicMedicalSciencesResearchCenteratBrandeis University,Waltham,Massachusetts. Charles H. Reynolds received his PhD in theoretical organic chemistry at the University of TexasatAustin.HeisaResearchFellowatJohnson&JohnsonPharmaceuticalResearchand Development,SpringHouse,Pennsylvania. Drug Design STRUCTURE- AND LIGAND-BASED APPROACHES Editedby KennethM.Merz,Jr. UniversityofFlorida,Gainesville DagmarRinge BrandeisUniversity,Waltham,Massachusetts CharlesH.Reynolds Johnson&JohnsonPharmaceuticalResearchandDevelopment, SpringHouse,Pennsylvania cambridgeuniversitypress Cambridge,NewYork,Melbourne,Madrid,CapeTown,Singapore, Sa˜oPaulo,Delhi,Dubai,Tokyo CambridgeUniversityPress 32AvenueoftheAmericas,NewYork,NY10013-2473,USA www.cambridge.org Informationonthistitle:www.cambridge.org/9780521887236 (cid:2)c CambridgeUniversityPress2010 Thispublicationisincopyright.Subjecttostatutoryexception andtotheprovisionsofrelevantcollectivelicensingagreements, noreproductionofanypartmaytakeplacewithoutthewritten permissionofCambridgeUniversityPress. Firstpublished2010 PrintedinChinabyEverbest AcatalogrecordforthispublicationisavailablefromtheBritishLibrary. LibraryofCongressCataloginginPublicationdata Drugdesign:structure-andligand-basedapproaches/editedbyKennethM.Merz, DagmarRinge,CharlesH.Reynolds. p. ; cm. Includesbibliographicalreferencesandindex. ISBN978-0-521-88723-6(hardback) 1.Drugs–Design. 2.Drugs–Structure-activityrelationships. I.Merz,KennethM.,1959– II.Ringe,Dagmar. III.Reynolds,CharlesH.,1957– IV.Title. [DNLM:1.DrugDesign. 2.Ligands. 3.Structure-ActivityRelationship. QV744D793272010] RS420.D793 2010 615′.19–dc22 2009051613 ISBN 978-0-521-88723-6Hardback CambridgeUniversityPresshasnoresponsibilityforthepersistenceor accuracyofURLsforexternalorthird-partyInternetWebsitesreferredtoin thispublicationanddoesnotguaranteethatanycontentonsuchWebsitesis, orwillremain,accurateorappropriate. Contents Contributors pagevii Preface ix 1 Progressandissuesforcomputationallyguidedleaddiscoveryandoptimization 1 WilliamL.Jorgensen PART I. STRUCTURAL BIOLOGY 2 X-raycrystallographyintheserviceofstructure-baseddrugdesign 17 GregoryA.PetskoandDagmarRinge 3 Fragment-basedstructure-guideddrugdiscovery:strategy,process,andlessons fromhumanproteinkinases 30 StephenK.Burley,GavinHirst,PaulSprengeler,andSiegfriedReich 4 NMRinfragment-baseddrugdiscovery 41 ChristopherA.Lepre,PeterJ.Connolly,andJonathanM.Moore PART II. COMPUTATIONAL CHEMISTRY METHODOLOGY 5 Free-energycalculationsinstructure-baseddrugdesign 61 MichaelR.Shirts,DavidL.Mobley,andScottP.Brown 6 StudiesofdrugresistanceandthedynamicbehaviorofHIV-1proteasethrough moleculardynamicssimulations 87 FangyuDingandCarlosSimmerling 7 Docking:adomesdayreport 98 MarthaS.Head 8 Theroleofquantummechanicsinstructure-baseddrugdesign 120 KennethM.Merz,Jr. 9 Pharmacophoremethods 137 StevenL.Dixon 10 QSARindrugdiscovery 151 AlexanderTropsha 11 PredictingADMEpropertiesindrugdiscovery 165 WilliamJ.Egan v vi Contents PART III: APPLICATIONS TO DRUG DISCOVERY 12 Computer-aideddrugdesign:apracticalguidetoprotein-structure-basedmodeling 181 CharlesH.Reynolds 13 Structure-baseddrugdesigncasestudy:p38 197 ArthurM.Doweyko 14 Structure-baseddesignofnovelP2-P4macrocyclicinhibitorsofhepatitis CNS3/4Aprotease 209 M.KatharineHollowayandNigelJ.Liverton 15 Purinenucleosidephosphorylasesastargetsfortransition-stateanalogdesign 215 AndrewS.MurkinandVernL.Schramm 16 GPCR3Dmodeling 248 FrankU.Axe 17 Structure-baseddesignofpotentglycogenphosphorylaseinhibitors 257 QiaolinDeng Index 265 Contributors FrankU.Axe MarthaS.Head AxeConsultingServices ComputationalandStructuralChemistry SutterCreek,California GlaxoSmithKlinePharmaceuticals Collegeville,Pennsylvania ScottP.Brown DepartmentofStructuralBiology GavinHirst AbbottLaboratories SGXPharmaceuticals AbbottPark,Illinois SanDiego,California StephenK.Burley M.KatharineHolloway SGXPharmaceuticals MolecularSystems SanDiego,California MerckResearchLaboratories WestPoint,Pennsylvania PeterJ.Connolly VertexPharmaceuticalsInc. WilliamL.Jorgensen Cambridge,Massachusetts DepartmentofChemistry YaleUniversity QiaolinDeng NewHaven,Connecticut DepartmentofMolecularSystems MerckResearchLaboratories ChristopherA.Lepre Merck&Co.Inc. VertexPharmaceuticalsInc. Rahway,NewJersey Cambridge,Massachusetts FangyuDing NigelJ.Liverton DepartmentofChemistry MedicinalChemistry CenterforStructuralBiology MerckResearchLaboratories StonyBrookUniversity WestPoint,Pennsylvania StonyBrook,NewYork KennethM.Merz,Jr. StevenL.Dixon DepartmentofChemistryand Schrodinger,Inc. QuantumTheoryProject NewYork,NewYork UniversityofFlorida Gainesville,Florida ArthurM.Doweyko ResearchandDevelopment DavidL.Mobley Computer-AssistedDrugDesign DepartmentofChemistry Bristol-MyersSquibb UniversityofNewOrleans Princeton,NewJersey NewOrleans,Louisiana WilliamJ.Egan JonathanM.Moore NovartisInstitutesforBioMedicalResearch VertexPharmaceuticalsInc. Cambridge,Massachusetts Cambridge,Massachusetts vii viii Contributors AndrewS.Murkin VernL.Schramm DepartmentofBiochemistry DepartmentofBiochemistry AlbertEinsteinCollegeofMedicine AlbertEinsteinCollegeofMedicine Bronx,NewYork Bronx,NewYork GregoryA.Petsko MichaelR.Shirts DepartmentofChemistry DepartmentofChemicalEngineering RosenstielBasicMedicalSciencesResearchCenter UniversityofVirginia BrandeisUniversity Charlottesville,Virginia Waltham,Massachusetts CarlosSimmerling SiegfriedReich DepartmentofChemistry SGXPharmaceuticals CenterforStructuralBiology SanDiego,California StonyBrookUniversity StonyBrook,NewYork CharlesH.Reynolds Johnson&JohnsonPharmaceuticalResearchand PaulSprengeler Development,LLC SGXPharmaceuticals SpringHouse,Pennsylvania SanDiego,California DagmarRinge AlexanderTropsha DepartmentofChemistry LaboratoryforMolecularModelingand RosenstielBasicMedicalSciencesResearch CarolinaCenterforExploratoryCheminformaticsResearch Center SchoolofPharmacy BrandeisUniversity UniversityofNorthCarolinaatChapelHill Waltham,Massachusetts ChapelHill,NorthCarolina Preface Our goal in producing this book is to provide a broad baseddesignreliescriticallyonstructural,computational, overview of the most important approaches used in andbiophysicalmethodstoidentify,characterize,andelab- protein- and ligand-structure-based drug design. Beyond oratesmalllow-affinityligands. thisweaimtoillustratehowtheseapproachesarecurrently The book is divided into three broad categories: struc- beingappliedindrugdiscoveryefforts.Wehopethisbook tural biology, computational chemistry, and drug discov- willbeausefulresourcetopractitionersinthefield,aswell eryapplications.Eachsectioncontainschaptersauthored asagoodintroductionforresearchersorstudentswhoare byacknowledgedexpertsinthefield.Althoughnobookof new to the field. We believe it provides a snapshot of the reasonablesizecanbecompletelycomprehensive,wehave most important trends and capabilities in the application attempted to address the most significant topics in each ofmodelingandstructuraldataindrugdiscovery. category,aswellassomeareasweseeasemergent.Weare Since the 1990s the role of structure and modeling in fortunate to have an introductory chapter from Professor drug discovery has grown enormously. There have been WilliamJorgensenthatsetsthetoneforthebook. remarkable scientific advances in both the experimen- Thestructuralbiologysectionbeginswithacomprehen- tal and computational fields that are the underpinnings sivereviewofthestrengthsandweaknessesofx-raycrystal- of modern drug design. For example, x-ray capabilities lography.Thisisthelogicalstartingpointformostprotein- have improved to the point that protein structures are structure-based design programs, as crystallography is now routinely available for a wide range of protein tar- certainly the most common approach for obtaining the gets. One only need look at the exponential growth of three-dimensional structures of therapeutically important the Protein Databank (RCSB) for evidence. Tremendous proteins. This section also includes two chapters on strides have been made in all aspects of protein struc- fragment-baseddrugdesign,includingonedevotedtothe turedetermination,includingcrystallization,dataacquisi- important role nuclear magnetic resonance has played in tion,andstructurerefinement.Modelinghasmadesimilar thisnewapproach. gains.Recentyearshavebroughtmorerealisticforcefields, The computational chemistry section covers a range newandmorerobustfree-energymethods,computational of modeling techniques, including free-energy methods, models for absorption/distribution/metabolism/excretion dynamics, docking and scoring, pharmacophore model- (ADME)-toxicity, faster and better docking algorithms, ing, quantitative structure/activity relationships, compu- automated 3D pharmacophore detection and searching, tational ADME, and quantum methods. Each topic was andvery-large-scalequantumcalculations.Whencoupled selected either because it is a commonly employed tool withtheinexorableincreaseincomputerpower,newand in drug discovery (e.g., docking and scoring) or because improvedcomputationalmethodsallowustoincorporate it is seen as an emerging technology that may have an modelingintothedrugdiscoveryprocessinwaysthatwere increasing role in the future (e.g., linear-scaling quantum notpossiblejustashorttimeago. calculations).Takentogether,thesechaptersprovideafairly In addition to improvements in methods, academic comprehensiveoverviewofthecomputationalapproaches and industrial groups have gained significant experience beingusedindrugdiscoverytoday. in the application of these approaches to drug discov- Thefinalsectiononapplicationsindrugdiscoverypro- eryproblems.Proteinstructures,docking,pharmacophore vides a few concrete examples of using the methods out- searches, and the like have all become a staple of drug lined in the first two sections for specific drug discovery discovery and are almost universally applied by large and programs.Thisistheultimatevalidationofanyexperimen- small pharma companies. A recent example of a new talorcomputationalapproach,atleastwithregardtodrug approach that is gaining wider acceptance is fragment- discovery.Theseexamplesfromsixdiverseproteintargets baseddrugdesign.Thegoaloffragment-baseddesignisto areusefultotheexpertasexamplesofbestpracticesandto buildupdrugcandidatesfromsmalllow-affinity,buthigh- thenoviceasexamplesofwhatcanbedone.Anoverview information-content, hit structures. As such, fragment- of G-protein-coupled receptor (GPCR) modeling and ix
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