Computational Methods for GPCR Drug Discovery

437 Pages·2018·17.589 MB·English

by  Alexander Heifetz (eds.)

Methods in
Molecular Biology 1705
Alexander Heifetz
Editor
Computational
Methods
for GPCR Drug
Discovery
M M B
ETHODS IN OLECULAR IO LO GY
SeriesEditor
JohnM.Walker
School of Lifeand MedicalSciences
University ofHertfordshire
Hatfield, Hertfordshire,AL109AB,UK
Forfurther volumes:
http://www.springer.com/series/7651
Computational Methods for GPCR
Drug Discovery
Edited by
Alexander Heifetz
Evotec (UK) Ltd., Abingdon, Oxfordshire, UK
Editor
AlexanderHeifetz
Evotec(UK)Ltd.
Abingdon,Oxfordshire,UK
ISSN1064-3745 ISSN1940-6029 (electronic)
MethodsinMolecularBiology
ISBN978-1-4939-7464-1 ISBN978-1-4939-7465-8 (eBook)
https://doi.org/10.1007/978-1-4939-7465-8
LibraryofCongressControlNumber:2017957977
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Preface
Gprotein-coupledreceptors(GPCRs)haveenormousphysiologicalandbiomedicalimpor-
tance,beingtheprimarysiteofactionofapproximately40%ofprescribeddrugs.Although
the human genome encodes more than 850 different GPCR proteins, to date drugs have
onlybeendevelopedagainst50ofthese.Thus,thereisauniqueopportunitytodesignnew
therapies for a huge number of unexploited but potentially tractable targets. Recent
advances in GPCR pharmacology and structural biology together with developments in
computational modeling have resulted in a resurgence in the number of GPCR drug
discoverycampaigns.
Thisbookprovidesauniqueoverviewofmoderncomputationalstrategiesandtechni-
quesemployedinthefieldofGPCRdrugdiscovery,includingstructure-andligand-based
approaches and cheminformatics. It is demonstrated how these computational approaches
can be used to address key issues in drug discovery such as receptor structure modeling,
protein-ligandinteractions,GPCRfunction,flexibilityanddynamics,ligandbindingkinet-
ics, positions of water molecules and their role in ligand binding, calculation of the free
energy of binding (affinity), prediction of the effects of mutations on ligand binding,
interconversionbetweenagonistsandantagonists,deorphanizationofGPCRs,anddiscov-
ery of biased and allosteric modulators. A review of these techniques will allow a diverse
audience, including structural and molecular biologists, computational and medicinal che-
mists,pharmacologistsanddrugdesigners,tonavigatethroughandeffectivelydeploythese
advances.
Abingdon,Oxfordshire,UK AlexanderHeifetz
v
Contents
Preface ..................................................................... v
Contributors................................................................. ix
1 CurrentandFutureChallengesinGPCRDrugDiscovery ................... 1
SidTopiol
2 CharacterizationofLigandBindingtoGPCRs
ThroughComputationalMethods ........................................ 23
SilvanaVasile,MauricioEsguerra,WillemJespers,AnaOliveira,
JessicaSallander,JohanA˚qvist,andHugoGutie´rrez-de-Tera´n
3 BreakthroughinGPCRCrystallographyandItsImpact
onComputer-AidedDrugDesign ........................................ 45
AntonellaCiancettaandKennethA.Jacobson
4 AStructuralFrameworkforGPCRChemogenomics:
What’sInaResidueNumber?............................................ 73
Ma´rtonVass,AlbertJ.Kooistra,StefanVerhoeven,
DavidGloriam,IwanJ.P.deEsch,andChrisdeGraaf
5 GPCRHomologyModelGenerationforLeadOptimization................. 115
ChristoferS.Tautermann
6 GPCRs:WhatCanWeLearnfromMolecularDynamicsSimulations? ......... 133
NaushadVelgy,GeorgeHedger,andPhilipC.Biggin
7 MethodsofExploringProtein–LigandInteractionstoGuide
MedicinalChemistryEfforts ............................................. 159
PaulLabute
8 ExploringGPCR-LigandInteractionswiththeFragment
MolecularOrbital(FMO)Method........................................ 179
EwaI.Chudyk,LaurieSarrat,MatteoAldeghi,DmitriG.Fedorov,
MikeJ.Bodkin,TimJames,MichelleSouthey,RogerRobinson,
InakiMorao,andAlexanderHeifetz
9 MolecularBasisofLigandDissociationfromGProtein-Coupled
ReceptorsandPredictingResidenceTime.................................. 197
DongGuoandAdriaanP.IJzerman
10 Methodologiesfor theExaminationofWaterinGPCRs..................... 207
AndreaBortolato,BenjaminG.Tehan,RobertT.Smith,
andJonathanS.Mason
11 MethodsforVirtualScreeningofGPCRTargets:Approaches
andChallenges ......................................................... 233
JasonB.Cross
12 ApproachesforDifferentiationandInterconvertingGPCR
AgonistsandAntagonists................................................ 265
PrzemysławMiszta,JakubJakowiecki,EwelinaRutkowska
MariaTurant,DorotaLatek,andSławomirFilipek
vii
viii Contents
13 OpportunitiesandChallengesintheDiscoveryofAllosteric
ModulatorsofGPCRs................................................... 297
DamianBartuzi,AgnieszkaA.Kaczor,andDariuszMatosiuk
14 ChallengesandOpportunitiesinDrugDiscoveryofBiasedLigands .......... 321
IsmaelRodrı´guez-Espigares, AgnieszkaA.Kaczor,TomaszMaciej
Stepniewski,andJanaSelent
15 SynergisticUseofGPCRModelingandSDMExperiments
toUnderstandLigandBinding........................................... 335
AndrewPotterton,AlexanderHeifetz,andAndreaTownsend-Nicholson
16 ComputationalSupportofMedicinalChemistryinIndustrialSettings ........ 345
DanielF.Ortwine
17 InvestigatingSmall-MoleculeLigandBindingtoGProtein-Coupled
ReceptorswithBiasedorUnbiasedMolecularDynamicsSimulations ......... 351
KristenA.MarinoandMartaFilizola
18 Ligand-BasedMethodsinGPCRComputer-AidedDrugDesign............. 365
PaulC.D.HawkinsandGuntherStahl
19 ComputationalMethodsUsedinHit-to-LeadandLeadOptimization
StagesofStructure-BasedDrugDiscovery................................. 375
AlexanderHeifetz,MichelleSouthey,InakiMorao
AndreaTownsend-Nicholson,andMikeJ.Bodkin
20 Cheminformatics intheServiceofGPCRDrugDiscovery................... 395
TimJames
21 ModelingandDeorphanizationofOrphanGPCRs ......................... 413
ConstantinoDiaz,PatriciaAngelloz-Nicoud,andEmiliePihan
Index ...................................................................... 431
Contributors
MATTEOALDEGHI (cid:1) Evotec(UK)Ltd.,Abingdon,Oxfordshire,UK
PATRICIAANGELLOZ-NICOUD (cid:1) ResearchInformatics,Evotec(France)SAS,Toulouse,France
˚
JOHANAQVIST (cid:1) DepartmentofCellandMolecularBiology,UppsalaUniversity,Biomedical
Center,Uppsala,Sweden
DAMIAN BARTUZI (cid:1) DepartmentofSynthesisandChemicalTechnologyofPharmaceutical
SubstanceswithComputerModellingLab,MedicalUniversityofLublin,Lublin,Poland
PHILIP C.BIGGIN (cid:1) DepartmentofBiochemistry,StructuralBioinformaticsand
ComputationalBiochemistry,UniversityofOxford,Oxford,UK
MIKEJ.BODKIN (cid:1) Evotec(UK)Ltd.,Abingdon,Oxfordshire,UK
ANDREA BORTOLATO (cid:1) HeptaresTherapeuticsLtd.,WelwynGardenCity,Hertfordshire,UK
EWAI.CHUDYK (cid:1) Evotec(UK)Ltd.,Abingdon,Oxfordshire,UK
ANTONELLACIANCETTA (cid:1) MolecularRecognitionSection,LaboratoryofBioorganic
Chemistry,NationalInstituteofDiabetesandDigestiveandKidneyDiseases,National
InstitutesofHealth,Bethesda,MD,USA
JASON B.CROSS (cid:1) UniversityofTexasMDAndersonCancerCenter,Houston,TX,USA
CONSTANTINODIAZ (cid:1) ResearchInformatics,Evotec(France)SAS,Toulouse,France
IWANJ.P.DEESCH (cid:1) DepartmentofMedicinalChemistry,AmsterdamInstituteforMolecules
MedicinesandSystems,VrijeUniversiteitAmsterdam,Amsterdam,TheNetherlands
MAURICIO ESGUERRA (cid:1) DepartmentofCellandMolecularBiology,UppsalaUniversity,
BiomedicalCenter,Uppsala,Sweden
DMITRIG.FEDOROV (cid:1) CD-FMat,NationalInstituteofAdvancedIndustrialScienceand
Technology(AIST),Ibaraki,Japan
SŁAWOMIRFILIPEK (cid:1) BiologicalandChemicalResearchCentre,FacultyofChemistry,
UniversityofWarsaw,Warsaw,Poland
MARTAFILIZOLA (cid:1) DepartmentofPharmacologicalSciences,IcahnSchoolofMedicineat
MountSinai,NewYork,NY,USA
DAVIDGLORIAM (cid:1) DepartmentofDrugDesignandPharmacology,Universityof
Copenhagen,Copenhagen,Denmark
CHRISDE GRAAF (cid:1) DepartmentofMedicinalChemistry,AmsterdamInstituteforMolecules
MedicinesandSystems,VrijeUniversiteitAmsterdam,Amsterdam,TheNetherlands
DONGGUO (cid:1) JiangsuKeyLaboratoryofNewDrugResearchandClinicalPharmacy,
XuzhouMedicalUniversity,Xuzhou,Jiangsu,China
HUGOGUTIE´RREZ-DE-TERA´N (cid:1) DepartmentofCellandMolecularBiology,Uppsala
University,BiomedicalCenter,Uppsala,Sweden
PAULC.D.HAWKINS (cid:1) OpenEyeScientificSoftware,SantaFe,NM,USA
GEORGEHEDGER (cid:1) DepartmentofBiochemistry,StructuralBioinformaticsand
ComputationalBiochemistry,UniversityofOxford,Oxford,UK
ALEXANDERHEIFETZ (cid:1) Evotec(UK)Ltd.,Oxfordshire,UK;DivisionofBiosciences,Research
DepartmentofStructuralandMolecularBiology,InstituteofStructuralandMolecular
Biology,UniversityCollegeLondon,London,UK
ADRIAANP.IJZERMAN (cid:1) DivisionofMedicinalChemistry,LeidenAcademicCentreforDrug
Research(LACDR),LeidenUniversity,Leiden,TheNetherlands
ix
x Contributors
KENNETHA.JACOBSON (cid:1) MolecularRecognitionSection,LaboratoryofBioorganicChemistry,
NationalInstituteofDiabetesandDigestiveandKidneyDiseases,NationalInstitutesof
Health,Bethesda,MD,USA
JAKUB JAKOWIECKI (cid:1) BiologicalandChemicalResearchCentre,FacultyofChemistry,
UniversityofWarsaw,Warsaw,Poland
TIMJAMES (cid:1) Evotec(UK)Ltd.,Abingdon,Oxfordshire,UK
WILLEMJESPERS (cid:1) DepartmentofCellandMolecularBiology,UppsalaUniversity,
BiomedicalCenter,Uppsala,Sweden
AGNIESZKAA.KACZOR (cid:1) DepartmentofSynthesisandChemicalTechnologyof
PharmaceuticalSubstanceswithComputerModellingLab,FacultyofPharmacywith
DivisionofMedicalAnalytics,MedicalUniversityofLublin,Lublin,Poland;Department
ofPharmaceuticalChemistry,SchoolofPharmacy,UniversityofEasternFinland,Kuopio,
Finland
ALBERTJ.KOOISTRA (cid:1) DepartmentofMedicinalChemistry,AmsterdamInstitutefor
MoleculesMedicinesandSystems,VrijeUniversiteitAmsterdam,Amsterdam,The
Netherlands;CentreforMolecularandBiomolecularInformatics(CMBI),Radboud
UniversityMedicalCenter,Nijmegen,TheNetherlands
PAULLABUTE (cid:1) ChemicalComputingGroupInc.,Montreal,QC,Canada
DOROTALATEK (cid:1) BiologicalandChemicalResearchCentre,FacultyofChemistry,University
ofWarsaw,Warsaw,Poland
KRISTEN A.MARINO (cid:1) DepartmentofPharmacologicalSciences,IcahnSchoolofMedicineat
MountSinai,NewYork,NY,USA
JONATHANS.MASON (cid:1) HeptaresTherapeuticsLtd.,WelwynGardenCity,Hertfordshire,UK
DARIUSZMATOSIUK (cid:1) DepartmentofSynthesisandChemicalTechnologyofPharmaceutical
SubstanceswithComputerModellingLab,MedicalUniversityofLublin,Lublin,Poland
PRZEMYSŁAWMISZTA (cid:1) BiologicalandChemicalResearchCentre,FacultyofChemistry,
UniversityofWarsaw,Warsaw,Poland
INAKIMORAO (cid:1) Evotec(UK)Ltd.,Abingdon,Oxfordshire,UK
ANAOLIVEIRA (cid:1) DepartmentofCellandMolecularBiology,UppsalaUniversity,Biomedical
Center,Uppsala,Sweden
DANIELF.ORTWINE (cid:1) DiscoveryChemistry,Genentech,Inc.,SouthSanFrancisco,CA,USA
EMILIEPIHAN (cid:1) ResearchInformatics,Evotec(France)SAS,Toulouse,France
ANDREWPOTTERTON (cid:1) StructuralandMolecularBiology,UniversityCollegeLondon,
London,UK;Evotec(UK)Ltd.,Oxfordshire,UK
ROGERROBINSON (cid:1) Evotec(UK)Ltd.,Abingdon,Oxfordshire,UK
ISMAELRODRI´GUEZ-ESPIGARES (cid:1) DepartmentofExperimentalandHealthSciences,Research
ProgrammeonBiomedicalInformatics(GRIB),HospitaldelMarMedicalResearch
Institute(IMIM),PompeuFabraUniversity(UPF),Barcelona,Spain
EWELINARUTKOWSKA (cid:1) BiologicalandChemicalResearchCentre,FacultyofChemistry,
UniversityofWarsaw,Warsaw,Poland
JESSICASALLANDER (cid:1) DepartmentofCellandMolecularBiology,UppsalaUniversity,
BiomedicalCenter,Uppsala,Sweden
LAURIESARRAT (cid:1) Evotec(UK)Ltd.,Abingdon,Oxfordshire,UK
JANA SELENT (cid:1) DepartmentofExperimentalandHealthSciences,ResearchProgrammeon
BiomedicalInformatics(GRIB),HospitaldelMarMedicalResearchInstitute(IMIM),
PompeuFabraUniversity(UPF),Barcelona,Spain
ROBERTT.SMITH (cid:1) HeptaresTherapeuticsLtd.,WelwynGardenCity,Hertfordshire,UK
MICHELLESOUTHEY (cid:1) Evotec(UK)Ltd.,Abingdon,Oxfordshire,UK
Contributors xi
GUNTHERSTAHL (cid:1) OpenEyeScientificSoftware,Ko¨ln,Germany
TOMASZMACIEJSTEPNIEWSKI (cid:1) DepartmentofExperimentalandHealthSciences,Research
ProgrammeonBiomedicalInformatics(GRIB),HospitaldelMarMedicalResearch
Institute(IMIM),PompeuFabraUniversity(UPF),Barcelona,Spain
CHRISTOFERS.TAUTERMANN (cid:1) DepartmentforMedicinalChemistry,BoehringerIngelheim
Pharma,GmbH&CoKG,BiberachanderRiss,Germany
BENJAMING.TEHAN (cid:1) HeptaresTherapeuticsLtd.,WelwynGardenCity,Hertfordshire,UK
SIDTOPIOL (cid:1) 3D-2drug,LLC,FairLawn,NJ,USA;Center forHealthcareInnovation,
StevensInstituteofTechnology,Hoboken,NJ,USA
ANDREATOWNSEND-NICHOLSON (cid:1) DivisionofBiosciences,ResearchDepartmentofStructural
andMolecularBiology,UniversityCollegeLondon,London,UK
MARIATURANT (cid:1) BiologicalandChemicalResearchCentre,FacultyofChemistry,University
ofWarsaw,Warsaw,Poland
SILVANAVASILE (cid:1) DepartmentofCellandMolecularBiology,UppsalaUniversity,Biomedical
Center,Uppsala,Sweden
MA´RTONVASS (cid:1) DepartmentofMedicinalChemistry,AmsterdamInstituteforMolecules
MedicinesandSystems,VrijeUniversiteitAmsterdam,Amsterdam,TheNetherlands
NAUSHADVELGY (cid:1) DepartmentofBiochemistry,StructuralBioinformaticsand
ComputationalBiochemistry,UniversityofOxford,Oxford,UK
STEFANVERHOEVEN (cid:1) NetherlandseScienceCenter,Amsterdam,TheNetherlands