Drug Design: Structure- and Ligand-Based Approaches

287 Pages·2010·7.224 MB·English

by  Kenneth M. Merz, Dagmar Ringe, Charles H. Reynolds

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
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(cid:2)c CambridgeUniversityPress2010
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noreproductionofanypartmaytakeplacewithoutthewritten
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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
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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