When fragments link: A bibliometric perspective on the development of fragment-based drug discovery - When fragments link

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When fragments link: A bibliometric perspective on the development of

fragment-based drug discovery

Romasanta, A.K.S.; van der Sijde, P.; Hellsten, I.; Hubbard, R.E.; Keseru, G.M.; van

Muilwijk-Koezen, J.; de Esch, I.J.P.

DOI

10.1016/j.drudis.2018.05.004

Publication date

2018

Document Version

Final published version

Published in

Drug discovery today

License

CC BY

Link to publication

Citation for published version (APA):

Romasanta, A. K. S., van der Sijde, P., Hellsten, I., Hubbard, R. E., Keseru, G. M., van

Muilwijk-Koezen, J., & de Esch, I. J. P. (2018). When fragments link: A bibliometric

perspective on the development of fragment-based drug discovery. Drug discovery today,

23(9), 1596-1906. https://doi.org/10.1016/j.drudis.2018.05.004

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Teaser

We

study

the

organizational

aspects

of

the

development

of

fragment-based

drug

discovery

(FBDD),

using

tools

from

bibliometrics.

When

fragments

link:

a

bibliometric

perspective

on

the

development

of

fragment-based

drug

discovery

Angelo

K.S.

Romasanta

1,2

,

Peter

van

der

Sijde

1

,

Iina

Hellsten

3

,

Roderick

E. Hubbard

4,5

,

Gyorgy

M. Keseru

6

,

Jacqueline

van

Muijlwijk-Koezen

2

and

Iwan

J.P.

de

Esch

2

1_Department_of_Science,_Business_&_Innovation,_Faculty_of_Science,_VU_University_Amsterdam,_De_Boelelaan_1105,

1081HVAmsterdam,TheNetherlands

2_Amsterdam_Institute_of_Molecules,_Medicines_and_Systems_(AIMMS),_Division_of_Medicinal_Chemistry,_VU

UniversityAmsterdam,DeBoelelaan1083,1081HVAmsterdam,TheNetherlands

3_Amsterdam_School_of_{Communication}_Research_(ASCoR),_University_of_Amsterdam,_Nieuwe_Achtergracht_166,

1018WVAmsterdam,TheNetherlands

4_Vernalis_Research,_Granta_Park,_Abington,_Cambridge_CB21_6GB,_UK

5_York_Structural_Biology_Laboratory,_Department_of_Chemistry,_University_of_York,_York_YO10_5DD,_UK

6_Research_Centre_for_Natural_Sciences,_Hungarian_Academy_of_Sciences,₁₁₁₇_Budapest,_Magyar_Tudósok_Körútja

2,P.O.Box17,Budapest1525,Hungary

Fragment-based

drug

discovery

(FBDD)

is

a

highly

interdisciplinary

field,

rich

in

ideas

integrated

from

pharmaceutical

sciences,

chemistry,

biology,

and

physics,

among

others.

To

enrich

our

understanding

of

the

development

of

the

field,

we

used

bibliometric

techniques

to

analyze

3642

publications

in

FBDD,

complementing

accounts

by

key

practitioners.

Mapping

its

core

papers,

we

found

the

transfer

of

knowledge

from

academia

to

industry.

Co-authorship

analysis

showed

that

university–

industry

collaboration

has

grown

over

time.

Moreover,

we

show

how

ideas

from

other

scientific

disciplines

have

been

integrated

into

the

FBDD

paradigm.

Keyword

analysis

showed

that

the

field

is

organized

into

four

interconnected

practices:

library

design,

fragment

screening,

computational

methods,

and

optimization.

This

study

highlights

the

importance

of

interactions

among

various

individuals

and

institutions

from

diverse

disciplines

in

newly

emerging

scientific

fields.

Introduction

FBDDisawidelyadoptedapproachtoleaddiscovery[1,2].Theoriginofthefieldcanbetraced back to its firstdemonstration20 yearsago at AbbottLaboratoriesby Shukeretal. [3].The historicaldevelopmentofFBDDhasbeendiscussedasanecdotes,forexampleduringlecturesat variousconferences[4]andinscientificpublications[5,6].Thetechnicalaspectsoftheapproach

Reviews KEYNO TE REVIEW AngeloK.S.Romasantais anearly-stageresearcheratthe MarieCurieITNFragNetbased attheChemistry& PharmaceuticalSciences DepartmentatVUUniversity Amsterdam.Withinthe divisionofScience,Business andInnovation,heisstudying

howcompaniesinthepharmaceuticalindustryabsorband applyexternalknowledgefromacademiaandotherfirms.Heis agraduateoftheErasmusMundusMasterinChemical InnovationandRegulationProgramundertheconsortiumof theUniversityofBarcelona,UniversityofAlgarve,and UniversityofBologna.

PetervanderSijdeisa professoroforganization, entrepreneurship&technology intheDepartmentofScience, Business&InnovationatVU UniversityAmsterdam,andhas abackgroundinsocialsciences. Hisresearchandteachingis focusedon(academic)

entrepreneurshipandtechnologytransfer. IinaHellstenisanassociate professorinsocialsciencesat theAmsterdamSchoolof CommunicationResearch (ASCoR)attheUniversityof Amsterdam.Shehasexpertise incommunicationnetworks, scienceandtechnologystudies (STS),andscientometrics. JacquelineE.van Muijlwijk-Koezenisaprofessorin innovationinhumanhealthand lifesciencesatVUUniversity Amsterdam.Hergroupaimsto applythetheoryofscience educationwithinthecontextof humanhealthandlifesciences. Herresearchfocuseson innovationsanddidacticsinscience

andeducation,withspecialemphasisinpharmaceutical sciencesanddrugdiscoveryresearchasembeddedwithinthe AmsterdamInstituteforMolecules,MedicinesandSystems. Researchonnewteachingconceptsandinnovativelearning approachesleadtonewinsightsthatareimplementedinthe variousstudyprogramsoftheFacultyofScience. IwanJP.deEschisa

professorinmedicinal chemistryatVUUniversity Amsterdamandheadofthe Chemistry&Pharmaceutical SciencesDepartment.Hiswork focusesontworesearchlines: G-protein-coupledreceptors andfragment-baseddrug

discovery(FBDD).Hehasco-foundedseveralacademic spin-outcompanies,includingDeNovoPharmaceuticals,Griffin Discoveries,andIOTAPharmaceuticals.

Correspondingauthor:deEsch,IwanJ.P. (i.de.esch@vu.nl)

1596 1359-6446/ã

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have also been described in key reviews[7–10]. Still,there are insightstobelearnedbysystematicallystudyinghowthefieldhas developed.Inthispaper,welookattheorganizationalandsocial aspectsofthedevelopmentofFBDDbyanalyzingscientific pub-licationsthatdescribenewdevelopmentsintheFBDDfieldand thereferencesthatareprovidedinthosepublications.Toanalyze theserecords,weusedbibliometrics,anapproachininformation sciencestoanalyzetherelationshipamongwrittenpublications. Previously,technological breakthroughs resulted from scien-tistsworkingtogetherattheinterfaceofdiversedisciplines, recom-biningknowledgefromvariousfields[11].TheemergenceofFBDD canbeseenasvariousscientificfieldscomingtogether,including computationalmethods,molecularbiology,biophysics,and me-dicinalchemistry.Withpharmaceuticalsciencesbeingmore mul-tidisciplinary and the pharmaceutical industry seeking more collaborations,especially in preclinicaldevelopment [12–14],it isappealingto investigatethe driversthathave madeFBDD so successful. With the increasing interest in how organizational factors can enable drug discovery [15], we seek to understand the rolesof variousgroups from industryand academiain the riseofFBDD.Bytracinghoweachpublicationfromacademiaand industryinfluencedthefield,wecanbetterunderstandtheroleof eachinstitutionindrivingforwardnewinnovations.

Finally,lookingatthetrendsinkeywordusageinthe publica-tionsovertimeandidentifyingwhichkeywordsusuallygo togeth-erinthesepublicationscanleadtoabettergraspofhowthefieldis organized.More importantly, by looking at the trends in each keywordovertime,wecangetasenseofhowthefocusofFBDD haschangedovertimeanditscurrentdirection.

Bibliometric

methods

Thepapersanalyzedinthisstudyweredownloadedfrom Thom-son-Reuter’s Web ofScience (WOS).To collect aninitial set of papers in the field of FBDD, keywords(Fig. 1) were used. The keywordsearchgenerated3208papers.Toensurethatthekeyword ‘fragment’wasusedtorefertothefield,welookedattheabstract, title,andkeywordfieldsofthepublicationsandtalliedthephrases that co-occurred the most with ‘fragment.’ We removed the combinationsthatwereunrelatedtothefield,resultinginadata setof2781papers.Toverifywhetherthesepaperswere represen-tative of FBDD, we inspected the data set and foundthat key publicationsinthefieldwerenotcapturedbythekeywordsusedin the preliminary search. Examples include Hopkins’s paper on ligandefficiency[16]andHann’spaperonmolecularcomplexity

[17], because these do not mention any of the keywords used (Fig.1).Thus,anadditionaldatacollectionstepwasperformed. Using the first set of papers, we checked for their most-cited references.Analyzingthereferences,weidentified861additional publicationsthatwerecitedatleasttentimes.Thislistcontained some publications that might not be directly related to FBDD developmentbutneverthelesshelpedtoshapethefield.An exam-pleisthemanyreferencestoBerman’spublicationdescribingthe ProteinDataBank(PDB),whichmarksthepivotalroleofprotein structuralinformation inFBDD[18].Merging thesepublication listsresultedin atotalof3642publications thatspantheyears from1953to2016.

TounderstandthedevelopmentofFBDD,wesetthehallmark publicationofShukeretal.[3]in1996asthestartingpointofour analysis.Weanalyzedpapersinthedatasetthatwerepublished

Fragment Fragment + + + Design discovery Ligand lead drug Library screening

Papers with unrelated keywords such as antibody fragment, gene fragment were removed

Minimum of ten citations

Initial data set

Filtering papers

Top cited

Total papers:

3642

+3208 papers

– 427 papers

+861 papers

Drug Discovery Today

FIGURE1

Datacollectionforfragment-baseddrugdiscovery(FBDD)publications.

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from1996to2016in5-yearintervals.Variousanalysesweredone toshowtheroleofpriorscientificknowledgeinadjacentfieldsand ofuniversity–industrycollaborationsin thedevelopmentofthe field.First,themost-citedarticlesinourdatasetofFBDDarticles were identified to find the core papers in FBDD. For further analysis, we used the software CitNetExplorer [19] to map the top 100 citedpapers, showing the citation relationship among them,allowingustotracetheevolutionofknowledge.Tostudy how collaborationbetweenacademia and industryhasevolved overthepast20years,wegeneratedco-authorshipnetworkmaps usingthesoftwareVosViewer[20].Touncoverthescientificroots ofFBDD,wealsoanalyzedthescientificfieldthattheFBDDarticles belonged to. Moreover, cluster analysis of keywords was per-formed. Byplotting a network map of keywordsthat co-occur in publications, we were able to identify the disciplines that researchersstudy.

Results

and

discussion

Emergence

as

‘fragment-based

drug

discovery’

Thefragment-basedapproachtodrugdevelopmentiswidely recog-nizedtohavestartedin1996,withitsfirstdemonstrationatAbbott Laboratories [3].This seminalpaperreferred to theapproach as ‘structure–activity relationship by nuclear magnetic resonance’ (SAR by NMR), for the first time demonstrating the detection, ranking,andprogressingofsmallandweak-affinitybinders.

Inouranalysis,theFBDDpublicationsinthefirst5yearsmostly operatedunderthegeneralumbrellaofdrugdiscoveryinsteadof distinguishing themselves as a particular discipline. However,

tracesofthekeywordsrelatedto FBDDwerepresentasearlyas the1990s,forexampleinthecomputationalworkofMoonand Howe[21]at Upjohn; Rotsteinand Murcko[22]atVertex; and Bo¨hm [23] at BASF. Synonyms, such as ‘needles’ and ‘needle screening’,usedtodescribeearlyapplicationsby Bo¨hmand co-workers,nowatF.Hoffmann-LaRoche[24],werenotadoptedby the scientificcommunity becausethese keywordswere usedin fewerthanfivepublicationsin anyyear.Asshown byFig.2,It wouldtakeafewmoreyearsbefore researchin thefield would cometogetherinatermsuchas‘fragment-baseddrugdiscovery’, whichfirstappearedintheabstractofthe2002paperbyMurray and Verdonk [25]. Even then, the field swopped between the keywords‘lead’and ‘drug’. The term‘lead discovery’dominate during the early years, stimulated by influential reviews from researchersatAstex[26–28]duringthemid-2000s.Differentiating between the two, the term ‘lead’ emphasizes the early stage whereinfragmentsareused(e.g.,beforepharmacokinetic proper-ties are being considered). By contrast, the term ‘drug’ can be helpfulinthatitcontextualizestheultimategoalthatfragments aimtoachieve,whichistodevelopdrugs.

By2009,theterm‘fragment-baseddrugdiscovery’hadfinally becomethetopkeywordthatresearchersusedtoidentifythefield, whereas‘leaddiscovery’hadlostfavorfromitspeakin2005,as shown inFig. 2.Asitcurrently stands, thefield isstilldivided between‘drugdiscovery’and‘drugdesign’.Discoveryrefersmore to the finding of a newdrug or drug candidate, whereasdrug designputsmoreemphasisontherationalapproachestobuildthe newdrug(candidate).Asitis,theabbreviationFBDDnowappears

Fragment-based drug discovery Fragment-based drug design Fragment-based lead design Fragment-based ligand design Fragment-based ligand discovery Fragment-based lead discovery

2004 2002 2006 2008 2010 2012 2014 2016 0 10 20 30 40 Year Occurrence

FIGURE2

Occurrenceoffragment-baseddrugdiscovery(FBDD)umbrellakeywordsintheliterature.Thesekeywordswerechosenbecausetheywerethetermsusedto

refertothefieldinvariousimportantreviews.

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to befavored over ‘fragment-baseddrug design’, beingused as muchasthreetimesmorein2016accordingtotheWebofScience, althoughthedifferentwordsappeartobeusedassynonyms.

Asidefromthemoreextensivekeyworduse,thegrowthofthe fieldisshownbylookingattheincreaseinnumberofpublications (Table1).Fromaninitialnumberof277publicationsinthefirst5 years,this increased sixfold to1709 publications from 2011to 2016.Therehasalsobeenanincreaseinthenumberofunique institutions, authors, and countries associated with the field, clearlyindicatingthatthe approach isbeingadoptedby an in-creasingnumberofscientists.

From

ideas

to

application:

the

role

of

industry

Clearly, industry has had a pivotal role in developing FBDD. AlthoughtheapproachwasfirstdemonstratedatAbbott Labora-tories[3],otherorganizationsin the privatesector were instru-mental in subsequent FBDD development, in particular by improvingemergingtechnologiesandapproachestoallowtheir applicationin drug discovery. Duringthe firstfew yearsofthe field,mostarticleswerepublishedbyindustryresearchers.Thisis noteworthy because an inherent bias towards universities is

expected when focusing on scientific publications, given the incentiveofacademicstopublish.Consideringthattheindustry hastheoppositeincentiveofwithholdinginformationfor com-petitive advantage [29,30], it emphasizes how influential the industrywasinthedevelopmentofFBDD.

Thisisalsosupportedbylookingatthetopinstitutesintermsof scientific impact, asmeasured by citations. As seenin Table2, especiallyforthefirstyearsofFBDD,theindustryclearlyledthe field.AbbottLaboratoriesdominatedduringthelate1990s.Astex (foundedin1999byUniversityofCambridgeprofessorsTom Blun-dell and Chris Abell and formerheadof structuralbiology and bioinformatics ofGlaxoWellcome, Harren Jhoti) led during the followingdecade.Onlyinthemost-recent5yearshastherebea surgeinpublicationsfromacademicsinthetop-tenlist.Table2also showsthatbiotechcompanies,suchasAstex,Vertex,andSunesis, havehadanimportantroleinestablishingthefield.However,some prominentbiotechsandpharmaceuticalcompaniesinFBDDdonot showupinthisparticularanalysisbecausetheymighthaveplaced lessemphasisonauthoringscientificpublications.

The important role of theprivate sector in FBDDinnovation is also apparentwhenlookingatthetop-tencitedpapersfromour

collec-TABLE1

SummaryoftheFBDDdatasetfrom1996to2016

Feature Timeframe

1996–2000 2001–2005 2006–2010 2011–2016

No.ofpublications 277 496 939 1709

No.ofjournals 95 143 220 363

No.ofresearchers(withaminimumoffivepublications)a ₁₀₂ ₁₉₀ ₃₄₃ ₃₈₉

No.oforganizations(withaminimumoftenpublications)a

No.ofacademicinstitutions 1 4 15 53

No.ofSMEs 0 3 3 6

No.ofbigpharmacompanies 1 7 7 7

a

Thisthresholdneededtobesetbecausesomefirmsandresearchersco-authorpublicationsbutdonotnecessarilypracticeFBDD.

TABLE2

TopinstitutionalpublishersandtheirtotalcitationsinthefieldofFBDDovertimea

Rank Timeframe 1996_–2001 2001_–2006 2006_–2011 2011_–2016 Institution No.of citations Institution No.of citations Institution No.of citations Institution No.of citations

1 AbbottLabs 154 Astex 368 Astex 595 OxfordUniversity 368

2 Vertex 77 AbbottLabs 221 Abbott 320 UniversityofCambridge 348

3 UniversityofCalifornia, SanFrancisco

52 Sunesis 187 UniversityofCalifornia,

SanFrancisco

261 GlaxoSmithKline 304

4 Roche 49 Novartis 163 AstraZeneca 249 Astex 232

5 Novartis 43 Pfizer 139 UniversityofCambridge 216 UniversityofCalifornia,

SanFrancisco

156 6 UniversityofSheffield 35 ScrippsInstitute 112 Novartis 188 AstraZeneca 139

7 BASF 34 AstraZeneca 93 ScrippsInstitute 187 Heptares 120

8 UniversityofCalifornia, SanDiego

29 GlaxoSmithKline 90 GlaxoSmithKline 184 Pfizer 110

9 UniversityofMarburg 28 SanfordBurnham 87 Pfizer 155 CancerResearchUK 105

10 CCDC 26 UniversityofCalifornia, SanFrancisco

85 Vernalis 135 UniversityofDundee 104

a

Academicgroupsareinred.

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tionofFBDDpapers(Table3).Nineofthetop-tenpublicationswere writtenbyindustryresearchers.Theonlypaperinthetoptenbyan academicisBerman’spublicationonthePDB[18],whichdoesnot strictly belong to FBDD butis a fundamental resourcefordrug discoveryresearchingeneralandforFBDDinparticularbecause manyofthehitfragmentoptimizationprogramshavebeenguided byproteinstructuraldata.Nexttosomeinfluentialreviews, includ-ingworkfromHajduk(previouslyAbbvie/Abbott),Congreve (pre-viouslyworkingforAstex),Rees(Astex)andErlanson(atthattime workingforSunesisPharmaceuticals),theconceptualLigand Effi-ciency(LE)workofHopkinsandco-workers(atthattimeworkingfor Pfizer)hashadanenormousimpact(rank2,Table3).LEassessesthe contributionofeveryatomtotheaffinityoftheligandandisusedto selectthemostpromisingfragmenthitsandtoguidethegrowingof fragmentsintobiggerdrug-likemolecules.Also,thetheoreticalwork ofHannandco-workersatGlaxoSmithKline(rank6,Table3)on understandinghowmolecularcomplexityimpactshitfindinghas been influential for FBDD. Among others, this work led to the realizationthatfragmentsshouldbesimpleandsmallmolecules thatcaninterrogatethebindingsiteswithhigherresolution.This alsoresultedintheguidelinescapturedinthe‘RuleofThree’,which define quality fragments. This popular mantra was attractively pitchedbyCongreveandco-workers(ranked4)asavariationon Lipinski’sRuleofFive(ranked7,Table3)thatdefinestheproperties ofdrug-likemolecules,theultimategoalofFBDDefforts.

However,if we lookat the top-citedjournals inrecent years (Table 4), seven out of the ten most-cited publications were authoredby academicfrom2009.Thisadoptionbyacademiais alsovalidatedbytheincreaseintheshareofpublishing universi-tiesandresearchinstitutionsinFBDDoverthepast5years.Oneof thereasonsfortheadoptionbyacademiaistheriseofacademic medicinalchemistryanddrugdiscoverygroups[12,31].Wecan alsospeculateon themobilityof researchers,includingexperts fromindustrywhomovetowardsuniversity,settingupacademic drugdiscoveryresearchgroups.Giventheincreaseininterestin howresearchermobilityaffectsinnovation[32],theimpactofthis mobilityandtransferofknowledgeonthedevelopmentofFBDD willbeatopicoffutureresearch.

Knowledge

transfer:

the

role

of

university

–industry

collaboration

Wethenexploredthelistofthetop100-citedarticlesinFBDD, representingthecorepapersofFBDD.Bycreatingacitationmapof thesearticlesovertime,wevisualizedtheevolutioninideaswithin FBDDandthechangingrolesofindustryandacademiainshaping theseideas.WhereasTable2andTable3revealthedominating roleoftheindustryinestablishingFBDD,theplotinFig.3reveals thatideasandtoolsdevelopedinacademiaprovidedgroundwork forthefield.

Mostofthe theoreticalgrounding of FBDDcame with ideas from academia as early as the 1970s. This early influence by

TABLE3

ThetenmostcitedpapersinthedatasetofFBDDarticlesa

Rank Authors Title Journal Affiliation Yearof

publication

No.of

citations

1 Shuker,S.B.,Hajduk,PJ.,

Meadows,R.P.,Fesik,S.W.

Discoveringhigh-affinityligandsfor

proteins:SARbyNMR

Science AbbottLabs 1996 454

2 Hopkins,A.L.,Groom,C.R.,Alex,A. Ligandefficiency:ausefulmetricfor

leadselection

DrugDiscoveryToday Pfizer 2004 403

3 Hajduk,P.J.,Greer,J. Adecadeoffragment-baseddrug

design:strategicadvancesand

lessonslearned

NatureReviewsDrug

Discovery

AbbottLabs 2007 353

4 Congreve,M.,Carr,R.,Murray,

C.,Jhoti,H.

Aruleofthreeforfragment-based

leaddiscovery?

DrugDiscoveryToday Astex 2003 342

5 Congreve,M.,Chessari,G.,Tisi,D.,

Woodhead,A.J.

Recentdevelopmentsin

fragment-baseddrugdiscovery

JournalofMedicinal

Chemistry

Astex 2008 290

6 Hann,M.M.,Leach,A.R.,Harper,G. Molecularcomplexityanditsimpact

ontheprobabilityoffindingleads

fordrugdiscovery

JournalofChemical

Informationand

ComputerScience

GlaxoSmithKline 2001 287

7 Lipinski,C.A.,Lombardo,F.,

Dominy,B.W.,Feeney,P.J.

Experimentalandcomputational

approachestoestimatesolubility

andpermeabilityindrugdiscovery

anddevelopmentsettings

AdvancedDrugDelivery

Reviews

Pfizer 1997 286

8 Rees,D.C.,Congreve,M.,Murray,

CW.,Carr,R

Fragment-basedleaddiscovery NatureReviewsDrug

Discovery

Astex 2004 275

9 Berman,H.M.,Westbrook,J.,Feng,

Z.,Gilliland,G.,Bhat,T.N.,Weissig,

H.,Shindyalov,I.N.,Bourne,P.E.

TheProteinDataBank NucleicAcidsResearch RutgersUniversity,

NationalInstituteof Standardsand Technology, BurnhamInstitute, Universityof California,SanDiego

2000 257

10 Erlanson,D.A.,McDowell,R.S.,

O’Brien,T.

Fragment-baseddrugdiscovery JournalofMedicinal

Chemistry

Sunesis 2004 219

a

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academiacan beseen explicitly with the paper of Jencksfrom BrandeisUniversity[33].Inhispaperontheadditivityofbinding energies,hesuggeststheideathatlargemoleculescanbe consid-eredasacombinationoffragments.

On the upper left side of the citation map, several papers authoredbyacademicscanalsobeseen.Thesearefoundational publications aboutinfluentialdrug discoverytools,suchasthe PDBin1977[34],moleculardockingapproachesbyFerrinand co-workersin1982[35],themolecularmodelingsoftwareCHARMM byKarplusandco-workersin1983[36],Goodford’scomputational procedurefordeterminingenergeticallyfavorablebindingsitesin 1988[37],andfunctionalitymapsofbindingsitesbyKarplusetal. in1991[38].Othercomputationalchemistryefforts(e.g.,Karplus, Schneider,andHubbard)todevelopdenovostructuregeneration and molecular docking softwarehave also madea tremendous impact.Frequently,thedevelopedalgorithmsusefragment-based approachesascomputational‘tricks’todissectthecomplicationof havingtoassessandweighthevariouspropertiesofbigger, drug-like compounds.During the early 1990s, the technologies and protocolsusedtodeterminefragmentbindingtoproteins,using, for example, sensitive biophysical technologies, were not yet available.Computationalapproacheswerealsoadoptedby indus-try,forexamplebySchneideratRocheandbothKlebeandBo¨hm at BASF. The latter scientistalso contributedto the pioneering needlescreeningworkatRochethatcombinesinsilicoapproaches

withbiochemicalandbiophysicalscreeningasanearlyexampleof fragment-basedapproachesinhitfindingandleaddevelopment. TheimpactofAbbottLaboratoriesondevelopingtheapplications isnotonlyapparentfromtheworkofFesikandco-workerswith NMRtechnology,butalsofromtheworkofGreerandco-workers, whichfocusesondiscoveringligandsusingX-raycrystallographic screening.Later, theircrystallographicscreeningmethod,called CrystaLEAD,wasfurther developedandexploitedbyinfluential scientistssuchasHubbard(UniversityofYork,Vernalis),Reesand Jhoti(Astex),andAbellandBlundell(UniversityofCambridge, co-foundersofAstex).Thesehigh-throughputX-raycrystallographic screening effortsweresupportedbyacademic activities,suchas the development by Cowtan and co-workers of the software COOT,aprogram thatisused todisplayelectrondensity maps andatomicmodels.

With academialaying outthe foundations ofFBDD and Big Pharmafirstdemonstratingthetechniquein1996,theroadwas nowreadyforthevalorizationofthefield.Thenextdecadeofkey FBDDpublicationscamealmostexclusivelyfromindustry. Espe-ciallyduringtheearly2000s,smallerstructure-baseddrug discov-erycompanies,suchasAstex,Vertex,andSunesis,cometohavean importantrole.ThesebiotechsspecializedinspecificFBDD tech-nologiesandapproaches(e.g.,crystalsoaking,biochemicalassays, andtethering)andperfectedthemforapplicationinhitfinding andleadgeneration.Fragmentsprovidedawayforthese

compa-TABLE4

Thetenmostcitedpaperspublishedfrom2009inthedatasetofFBDDarticlesa

Rank Authors Title Journal Affiliation Yearof

publication

No.of

citations

1 Murray,CW.,Rees,D.C. Theriseoffragment-baseddrug

discovery

NatureChemistry Astex 2009 141

2 Chessari,G.,Woodhead,A.J. Fromfragmenttoclinical

candidate-ahistorical

perspective

DrugDiscoveryToday Astex 2009 82

3 Murray,C.W.,Verdonk,M.L., Rees,D.C. Experiencesinfragment-based drugdiscovery TrendsinPharmacological Sciences Astex 2012 76

4 Scott,D.E.,Coyne,A.G.,

Hudson,S.A.,Abell,C.

Fragment-basedapproachesin

drugdiscoveryandchemical

biology

Biochemistry UniversityofCambridge 2012 75

5 Murray,C.W.,Blundell,T.L. Structuralbiologyin

fragment-baseddrugdesign

CurrentOpinionInStructural

Biology

UniversityofCambridge, Astex

2010 70

6 deKloe,G.E.,Bailey,D.,Leurs,

R.,deEsch,I.J.P.

Transformingfragmentsinto

candidates:smallbecomesbig

inmedicinalchemistry

DrugDiscoveryToday IOTA,VrijeUniversity,

Amsterdam

2009 69

7 Filippakopoulos,P.,Bradner,

J.E.etal.

SelectiveinhibitionofBET

bromodomains

Nature DanaFarberCancer

Institute,Harvard University,Universityof NotreDame,Oxford University

2010 68

8 Baker,M Fragment-basedleaddiscovery

growsup

NatureReviewsDrug

Discovery

2013 67

9 Emsley,P.,Lohkamp,B.,

Scott,W.G.,Cowtan,K.

Featuresanddevelopmentof

Coot ActaCrystallographica SectionDBiological Crystallography KarolinskaInstitute, UniversityofYork, UniversityofCalifornia, SantaCruz,Oxford University

2010 67

10 Chen,Y.,Shoichet,B.K. Moleculardockingandligand

specificityinfragment-based

inhibitordiscovery

NatureChemicalBiology UniversityofCalifornia

SanFrancisco

2009 62

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Academia

Industry

Collaboration

1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

FIGURE3

Citationmapof100corepapersinfragment-baseddrugdiscovery(FBDD).Eachpaperislabeledbyitslastauthor.Colorsreflecttheaffiliationoftheauthors;

squareshighlightreviewarticles.

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niestoobtainhits withoutthe needto investmillionsin com-pound libraries and robotics that are needed for typical high-throughputscreening(HTS)approaches[6].Notallknown tech-nologiesandFBDDcompaniesappearinthisbibliometricanalysis, possiblybecauseoftheirrestrictedeffortstopublishinscientific literature.Itisinterestingthatthosecompaniesthatdopublish makeasignificantimpactwhenconsideringcollaborationsthat publishFBDDwork(Fig.4).

During the early years of FBDD, most institutions involved were carrying out research independently.During this period, onlyasmallgroupofmostlyacademicinstitutionswere collabo-ratingwithafewplayersintheindustry(Fig.4a).Thisisseenby the mostly fragmented nodes on the right side of the plot. However,bytheearly 2000s, a networkofuniversity–industry collaborations started to form (Fig. 4b). With the research in FBDD becoming more collaborative, institutions from big

(a) 1996–2000 (b) 2001–2005

FIGURE4

Collaborationnetworkmapoftop500publishinginstitutionsinfragment-baseddrugdiscovery(FBDD)groupedin5-yearperiodsfrom1996to2016.Eachnode

correspondstoaninstitution.Thesizereflectsthenumberofpublications.Rednodesarefromacademia,whereasbluenodesarefromindustry.Dark-bluenodes

arefrombigpharma,whereaslight-bluenodesareotherindustrialfirms,includingsmallbiotechsandfirmsfromadjacentindustries.Fortheyears2006_–2016,

thebiggestclusterisshown.

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pharma,spinoffs,andacademiaco-authoredanincreasing num-berofarticles.Especiallyfrom2011to2016,agreaterdegreeof integrationamongpracticinginstitutionscanbeobserved.The tightintegrationshowsthatFBDDisahigh-techand

multidisci-plinaryresearchfieldinwhichspecialistsinvariousresearchareas collaborate in developing new pharmaceuticals. The develop-ment of this field also coincides with the transition of the pharmaceuticallandscapeinwhichthebigcompaniesoutsource

1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Methods

Molecular basis

Applications

Crystallography

FIGURE5

Citationmapof100corepapersinfragment-baseddrugdiscovery(FBDD).Thecolorsshowclusteringofpapersbysimilarity.

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moreoftheirpreclinicalresearch[39,40],animportantchange thatappearstohaveshapedtheFBDDfield.

Recombining

knowledge

from

other

scientific

fields

To further understand howFBDD integrates knowledge from various scientificdisciplines,wemanuallyclassifiedthepreviouscorepapers according to theircontent anddiscipline of origin, as shown inFig.5. Before1996,thescientificgroundworkthatwouldeventuallybe integratedinFBDDcamefromtwoseparatefronts.Asseenonthe upperrightsideofFig.5,atoneend,wehavetheworkofJencks, whichprovidedthetheoreticalrationalizationforfragments.Atthe otherend(greenclusterofFig.5),thepreviouslydiscussed meth-odologiesthatarefundamentalinFBDDresearchcanbeseen.These computationalapproachesformanindependentbranchthatused fragmentapproachesinbindingenergy calculationsand denovo structuregeneration software.As seenin Fig. 5,there is a clear separationbetweenthesetwobrancheswithnopapercitingthe twobeforeFesik’shallmarkpublication.

Thus, it shows how keythe SAR by NMR Science paper by Fesik and co-workerswasinjumpstartingthefield.AsshowninFig.5,the paperservesasahubfromwhichadenseamountofpublications branch.ThepublicationbyFesikbroughtthetwoseparatebranches together,explicitlyreferringtothepaperofJenckswhilealso refer-ringtoBohm’s LUDI[23],Hubbard’sHOOK [41],and Murcko’s GroupBuild[22]atthesametime.Thus,thetheoretical consider-ationsandthecomputer-aideddrugdesigncapabilitieswere com-bined,enabledbytheemergingbiophysicalscreeningtechnologies (e.g.,NMR)andcombinedwithX-raycrystallographytomeasure andvisualize,respectivelylow-affinityfragmentbinding.

We looked at the categories of the journal sources of FBDD papers.DoingsoallowedustoseethedisciplinesthatFBDDwas buildingfrom.InFig.6,before1995,FBDDliteraturecitedarticles from the fields of biophysics, biochemistry, molecular biology, andcomputerscience.Thissignaledthatadvancementsin knowl-edgeinthesevariousfrontswasnecessaryforFBDDtoexpand.It alsogaveaclearindicationthatFBDDisenteringmainstreamwith manypublicationsnowappearinginthemoreappliedmedicinal chemistryfield,whereasduringtheearlyyears,mostpaperswere inthefieldsofbiochemistry,molecularbiology,biophysics,and computationalchemistry.

Althoughthisclusterincludesthepre-1990scomputational tech-niquesdescribedpreviously,theinfluenceofthisclusterextends into theearly2000s,includingde novostructuregenerationand dockingalgorithms,suchasGlide[42]in2004andthedevelopment offrequentlyuseddatabases,suchasZINC[43]in2005.

Referring back to Fig. 5, the blue cluster on the right side compriseswhatareconsideredtobeintegralFBDDpublications. Theseincludeprinciplesanddemonstrationsofhowvarious bio-physicaltechniquescanbeusedintheparadigmofFBDD.Also includedareapplicationsofFBDDtovarioustherapeutictargets(i. e., the actual use in drug discovery [44,45]). Moreover, it also includes16keyreviewsthatsummarizeandintegrateknowledge inthefield.

WealsoseeavioletclusterattheearlystagesofFBDDfrom1996 to2002,whichdescribesconceptsrelatingtothemolecularbasis of the approach.One wayofinterpreting this isthat thereare researchers(suchasFesik)whobridgethegapbetweenanewfield and establishedmethods, in this case providingthe molecular

Medicinal chemistry

Biochemistry and molecular biology Chemistry (general)

Pharmacology and pharmacy Biochemical research methods Computer science (applications)

Computer science (information systems) Biophysics Organic chemistry 2000 1500 1000 500 0 Pre–1995 1996–2000 2001–2005 2006–2010 2011–2016 Years 3-year citations

FIGURE6

Categoriesofjournalsovertime.

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basis of FBDD. By formulating principles from their outsider perspective, these researchers are able to integrate previously unexploitedknowledgeandtechnologiesintothegrowingbody ofFBDDliterature.Theimportantroleofkeyopinionleaderscan beseeninthecentralpartoftheplot,whereapproximately2005 scientists,suchasRees,Jhoti,andAbell(AstexandUniversityof Cambridge),Hubbard(UniversityofYorkandVernalis),Fesikand Hajduk (AbbottLaboratories), andErlanson (Sunesis),explicitly integratethevariousaspectsofFBDDintheirpublications.

The citation map also shows an orange cluster, which was integrated intoFBDD relativelymorerecently.Thesearepapers inthefieldofcrystallography,suchastheCCP4suite[46]in1994, Minor’sprocessing ofX-ray diffractiondata[47],and Dodson’s refinementofmacromolecularstructures[48],bothin1997.

TheimpactthatcrystallographywouldhaveonFBDDis continu-ing.Byanalyzingthekeywordsusedintheabstractandtitleofthe publicationsinthefield,wecangetasenseofthemethodsthatcatch the interestof practitioners.Asseen in Fig.7, althoughnuclear magnetic resonance (NMR)was the dominanttechnique during thefirstyearsofFBDD,ithasbeenreplacedbyX-raycrystallography over the past 5 years.However, this does not perfectly reflectthe usage ofsuchtechniques invariouslaboratories,butratherreflectsthe identifiers thatare usedby authors to attracttheir targetedreadership. Currently,thefieldisorganizedintofourinterrelatedpractices. Todeterminethesefourclassifications,thetopkeywordsinFBDD was plotted and clustered according to how often they occur together per paper (Fig. 8). Four clusters were detected, corre-sponding to the four major fields working together in FBDD: molecular biology, (medicinal) chemistry, biophysics, and

computationalchemistry.Theseinturnaidthe majorprocesses inFBDD,namely,designingthefragmentlibrary,screeningthem using, for example, biophysical techniques, modeling using computationalmethods,andoptimizingthelead.Althoughthe position of the keywords generally indicates the category and interrelatednessofthekeywords,thepositionmustbetakenwith ‘agrainofsalt’becausekeywordsaremoreoftenthannotrelated tothethreeotherdimensionsofFBDD.

ToseethetrendsinFBDDovertheyears,thesekeywordswere coloredaccordingtotheaverageyearofpublication.Asshownin

Fig. 8, the colors correspond to the average year of keyword occurrence.Interestingly,thereisatrendtowardstheupperleft clusterofmolecularbiology,withmorekeywordsoccurringmore recently. This is expected because the field has been moving towardsapplyingFBDD,insteadofbuildingbasicknowledgethat comesfromtheotherclusters.

AsFBDDmatures,ithasbeenappliedtomoretargets.Thiscan beseenby the curious caseofthe publicationby Bradner [49]. GoingbacktoFig.5,thispublicationdoesnotcitethecoreFBDD literature,yetiscitedbymanyoftherecentpapersinFBDD.This publicationontheinhibitionofBETbromodomainshasbeenan areaofinterestforFBDDresearchersinrecentyears.

Togetherwithothertargets,thefocusnowforFBDDhasbeenits application.Themostcitedreferencesinrecentyears(asseenin

Table4)havebeenreviewsshowinghowanincreasingnumberof leadsoriginatingfromFBDDareenteringclinicaltrials.Itisnot only industry using the technique, but also various academic groups.WiththegrowthofFBDD,smallhasindeedbecomebig indrugdiscovery[10].

X-ray crystallography Surface plasmon resonance Nuclear manetic resonance Thermal shift assay

Isothermal titration calorimetry Mass spectrometry 3-year citations 500 400 300 200 100 0 _1996–2000 _2001–2005 _2006–2010 _2011–2016 Years

FIGURE7

Occurrenceofvarioustechniquesinfragment-baseddrugdiscovery(FBDD)papersovertime.

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Concluding

remarks

Here,wehaveshownthehistoryofFBDDbyusingbibliometric methods.Duringtheearlydaysofthefield,researchinFBDDwas highlyfragmented,operatingunderthegeneralumbrellaofdrug discovery.Today,scientificprogressinFBDDareorganizedwith the leading keywords ‘fragment-based lead discovery’ (FBLD), ‘fragment-based drug discovery’, and ‘fragment-based drug design.’Althoughthese termsall refertothe sameapproaches, theyputemphasisondifferentaspectsofworkandtheultimate aimoftheendeavors.

ThehistoryofFBDDprovidesasolidcaseforhowrecombining knowledgefromvariousworldscanadvancescience.Thiswasseen at two levels. First, on the organizational level, industry and academiaplayedtheirrespectiverolesreliablywell.Academialaid

downthetheoreticalfoundationsandalsogeneratedresearchon methodsthatcouldbelaterimplemented industrially.Withthe basicsciencelaidout,industrywasabletovalorizetheknowledge andintegrateitintoactualdrugdiscoveryefforts.ProgressinFBDD wasabletooccuralongsideagrowinginterconnectednetworkof collaborations among various institutions. The studies clearly identify an increasing interconnectedness between academia and industry. Interestingly, FBDD researchfield has developed overthesameyearsthatthe pharmaceuticalresearchlandscape hasundergonemajorchanges, withbigpharmaceutical compa-nies outsourcing an increasing amount of preclinical research work [50].As such, FBDDforms aninterestingtopic to further explorebusinessdevelopmentandinnovationmanagementinthe pharmaceutical sciences. Using the bibliometric database as a

Molecular biology

Chemistry

Computational

Biophysics

2004 2006 2008 2010 2012

FIGURE8

Occurrencenetworkoftop100keywordsinfragment-baseddrugdiscovery(FBDD).Colorcorresponstotheaverageyearofoccurrenceofeachkeyword.

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premise,wewouldliketodeepenunderstandingofhow collabora-tionsareformed.Also,withcollaborationsinFBDDincreasing,itis ofvaluetounderstandhowthesecollaborationsaremaintainedso that all thecomplementaryabilities ofeachpartnersare syner-gized instead of workingseparately. Finally, it is of essence to evaluatethesuccessoftheseinitiativestowardsopeninnovation. ThetechnicalaspectofthedevelopmentofFBDDshowsusthat integrationofoutsidertechnologieswithsolidtheoretical ground-ingisausefulapproachtoinnovation.Beingabletospot oppor-tunities for integrating is becoming a more valuable skill for researcherswantingtostayontopoftheirfields.Itisofinterest thentounderstandhowbothacademiaandindustrycopewith thisneed.Furthersurveysshouldbedoneonthisfront.

Futurestudiesshouldalsoaddressthelimitationsofourcurrent approach.Inthisbibliometricanalysis,weonlyfocusedonscientific publications in FBDD. This analysis identified the key opinion leaders of the field and publications that are accessible to the world-wideresearchcommunitymakeanobviousimpact.However,

certainkeycontributionstotheFBDDfieldareexcludedfromthe analysis.Given thatpharmaceuticalcompanies andbiotechsare oftennotincentivizedtopublish,analyzingthepatentlandscape mightbeabletocharacterizebetterthecurrentstateof collabora-tionsinthefield.Collectingadditionaldatasources,suchas com-panydisclosures,conferenceattendance,andnewchemicalentities inthemarket,couldprovideacomprehensivepictureofthegrowth ofFBDD.Byconnectingandanalyzingthesedatatogether,itwould bepossibletobetterunderstandthefactorsthatallowcompaniesto successfullybringtheirlaboratoryresultstothemarket.Webelieve thatbuildingabetterunderstandingofbusinessdevelopmentand innovationmanagementinsuchawell-definedandrecently devel-opedresearchareaasFBDDoffersusefulcasestudiestodescribethe changinglandscapeofpharmaceuticalsciences.

Acknowledgment

ThisworkwassupportedbytheEuropeanUnion’sHorizon2020 MSCAProgramundergrantagreement675899(FRAGNET).

References

1Murray,C.andRees,D.C.(2009)Theriseoffragment-baseddrugdiscovery.Nat. Chem.1,187–192

2Baker,M.(2013)Fragment-basedleaddiscoverygrowsup.Nat.Rev.DrugDiscov.12, 5–7

3Shuker,S.B.etal.(1996)Discoveringhigh-affinityligandsforproteins:SARbyNMR. Science274,1531

4Nowak,T.andHubbard,R.E.(2013)IntroductiontoFBDD.InFragmentsWorkshop

2013,p.6,Publisher

5Chessari,G.andWoodhead,A.J.(2009)Fromfragmenttoclinicalcandidate:a historicalperspective.DrugDiscov.Today14,668–675

6Hammonds,T.andSimpson,P.B.(2015)TheHandbookofMedicinalChemistry: PrinciplesandPractice.TheRoyalSocietyofChemistry

7Keseru˝,G.M.etal.(2016)Designprinciplesforfragmentlibraries:maximizingthe valueoflearningsfrompharmafragment-baseddrugdiscovery(FBDD)programsfor useinacademia.J.Med.Chem.59,8189–8206

8Erlanson,D.A.etal.(2016)Twentyyearson:theimpactoffragmentsondrug discovery.Nat.Rev.DrugDiscov.15,605–619

9Hall,R.J.etal.(2014)Efficientexplorationofchemicalspacebyfragment-based screening.Prog.Biophys.Mol.Biol.116,82–91

10deKloe,G.E.etal.(2009)Transformingfragmentsintocandidates:smallbecomes biginmedicinalchemistry.DrugDiscov.Today14,630–646

11Keijl,S.etal.(2016)Thetwofacesofinventions:therelationshipbetween recombinationandimpactinpharmaceuticalbiotechnology.Res.Policy45, 1061–1074

12Tralau-Stewart,C.J.etal.(2009)Drugdiscovery:newmodelsforindustry–academic partnerships.DrugDiscov.Today14,95–101

13Schuhmacher,A.etal.(2013)Modelsforopeninnovationinthepharmaceutical industry.DrugDiscov.Today18,1133–1137

14Ekins,S.etal.(2013)Fourdisruptivestrategiesforremovingdrugdiscovery bottlenecks.DrugDiscov.Today18,265–271

15Sams-Dodd,F.(2005)Optimizingthediscoveryorganizationforinnovation.Drug Discov.Today10,1049–1056

16Hopkins,A.L.etal.(2004)Ligandefficiency:ausefulmetricforleadselection.Drug Discov.Today9,430–431

17Hann,M.M.etal.(2001)Molecularcomplexityanditsimpactontheprobabilityof findingleadsfordrugdiscovery.J.Chem.Inf.Comput.Sci.41,856–864

18Berman,H.M.etal.(2000)TheProteinDataBank.NucleicAcidsRes.28,235–242

19vanEck,N.J.andWaltman,L.(2014)CitNetExplorer:anewsoftwaretoolfor analysingandvisualizingcitationnetworks.J.Informetr.8,802–823

20VanEck,N.J.andWaltman,L.(2010)Softwaresurvey:VOSviewer,acomputer programforbibliometricmapping.Scientometrics84,523–538

21Moon,J.B.andHowe,W.J.(1991)Computerdesignofbioactivemolecules:a methodforreceptor-baseddenovoliganddesign.ProteinsStruct.Funct.Bioinf.11, 314–328

22Rotstein,S.H.andMurcko,M.A.(1993)GroupBuild:afragment-basedmethodfor denovodrugdesign.J.Med.Chem.36,1700–1710

23Bo¨hm,H.-J.(1992)ThecomputerprogramLUDI:anewmethodforthedenovo designofenzymeinhibitors.J.Comput.AidedMol.Des.6,61–78

24Boehm,H.-J.etal.(2000)NovelinhibitorsofDNAgyrase:3Dstructurebasedbiased needlescreening,hitvalidationbybiophysicalmethods,and3Dguided optimization.Apromisingalternativetorandomscreening.J.Med.Chem.43, 2664–2674

25Murray,C.W.andVerdonk,M.L.(2002)Theconsequencesoftranslationaland rotationalentropylostbysmallmoleculesonbindingtoproteins.J.Comput.Aided Mol.Des.16,741–753

26Hartshorn,M.J.etal.(2005)Fragment-basedleaddiscoveryusingX-ray crystallography.J.Med.Chem.48,403–413

27Rees,D.C.etal.(2004)Fragment-basedleaddiscovery.Nat.Rev.DrugDiscov.3, 660–672

28Carr,R.A.E.R.etal.(2005)Fragment-basedleaddiscovery:leadsbydesign.Drug Discov.Today10,987–992

29Dasgupta,P.andDavid,P.A.(1994)Towardaneweconomicsofscience.Res.Policy 23,487–521

30Lexchin,J.etal.(2003)Pharmaceuticalindustrysponsorshipandresearchoutcome andquality:systematicreview.BMJ326,1167–1170

31Frye,S.etal.(2011)USacademicdrugdiscovery.Nat.Rev.DrugDiscov.10,409–410

32Azoulay,P.etal.(2017)Themobilityofelitelifescientists:professionalandpersonal determinants.Res.Policy46,573–590

33Jencks,W.P.(1981)Ontheattributionandadditivityofbindingenergies.Proc.Natl. Acad.Sci.U.S.A.78,4046–4050

34Bernstein,F.C.etal.(1977)Theproteindatabank.Eur.J.Biochem.80,319–324

35Kuntz,I.D.etal.(1982)Ageometricapproachtomacromolecule-ligand interactions.J.Mol.Biol.161,269–288

36Brooks,B.R.etal.(1983)CHARMM:aprogramformacromolecularenergy, minimization,anddynamicscalculations.J.Comput.Chem.4,187–217

37Goodford,P.J.(1985)Acomputationalprocedurefordeterminingenergetically favorablebindingsitesonbiologicallyimportantmacromolecules.J.Med.Chem.28, 849–857

38Miranker,A.andKarplus,M.(1991)Functionalitymapsofbindingsites:amultiple copysimultaneoussearchmethod.ProteinsStruct.Funct.Bioinf.11,29–34

39Kneller,R.(2010)Theimportanceofnewcompaniesfordrugdiscovery:originsofa decadeofnewdrugs.Nat.Rev.DrugDiscov.9,867–882

40Wang,L.etal.(2015)RacingtodefinepharmaceuticalR&Dexternalinnovation models.DrugDiscov.Today20,361–370

41Eisen,M.B.etal.(1994)HOOK:aprogramforfindingnovelmoleculararchitectures thatsatisfythechemicalandstericrequirementsofamacromoleculebindingsite. ProteinsStruct.Funct.Bioinf.19,199–221

42Friesner,R.A.etal.(2004)Glide:anewapproachforrapid,accuratedocking andscoring.1.Methodandassessmentofdockingaccuracy.J.Med.Chem.47, 1739–1749

43Irwin,J.J.andShoichet,B.K.(2005)ZINC-afreedatabaseofcommerciallyavailable compoundsforvirtualscreening.J.Chem.Inf.Model.45,177–182

Reviews

KEYNO

TE

(15)

44Hajduk,P.J.etal.(1997)Discoveryofpotentnonpeptideinhibitorsofstromelysin usingSARbyNMR.J.Am.Chem.Soc.119,5818–5827

45Oltersdorf,T.etal.(2005)AninhibitorofBcl-2familyproteinsinducesregressionof solidtumours.Nature435,677–681

46CollaborativeComputationalProject4(1994)TheCCP4suite:programsforprotein crystallography.ActaCrystallogr.DBiol.Crystallogr.50,760

47Otwinowski,Z.andMinor,W.(1997)ProcessingofX-raydiffractiondatacollected inoscillationmode.MethodsEnzymol.276,307–326

48Murshudov,G.N.etal.(1997)Refinementofmacromolecularstructuresbythe maximum-likelihoodmethod.ActaCrystallogr.DBiol.Crystallogr.53,240–255

49Filippakopoulos,P.etal.(2010)SelectiveinhibitionofBETbromodomains.Nature 468,1067–1073

50Fishburn,C.S.(2013)Translationalresearch:thechanginglandscapeofdrug discovery.DrugDiscov.Today18,487–494

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