Table Of ContentFrontiers in Molecular Design and
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ACS Symposium Series; American Chemical Society: Washington, DC, 2016.
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Bienstock et al.; Frontiers in Molecular Design and Chemical Information Science - Herman Skolnik Award Symposium 2015: ...
ACS Symposium Series; American Chemical Society: Washington, DC, 2016.
1222
ACS SYMPOSIUM SERIES
Frontiers in Molecular Design and
Chemical Information Science -
Herman Skolnik Award
Symposium 2015:
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w Jürgen Bajorath
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1/b Rachelle J. Bienstock, Editor
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1 RJB Computational Modeling LLC
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oi: North Carolina State University
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01 Veerabahu Shanmugasundaram, Editor
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DistributedinprintbyOxfordUniversityPress
Bienstock et al.; Frontiers in Molecular Design and Chemical Information Science - Herman Skolnik Award Symposium 2015: ...
ACS Symposium Series; American Chemical Society: Washington, DC, 2016.
LibraryofCongressCataloging-in-PublicationData
Names:HermanSkolnikAwardSymposium(2015:Boston,Mass.)|Bienstock,
RachelleJ.,editor.|Shanmugasundaram,Veerabahu,editor.|Bajorath,Jürgen,
editor.|AmericanChemicalSociety.DivisionofChemicalInformation.
Title:Frontiersinmoleculardesignandchemicalinformationscience:Herman
SkolnikAwardSymposium2015:JürgenBajorath[recipient]/RachelleJ.
Bienstock,editor,RJBComputationalModelingLLC,NorthCarolina
StateUniversity,VeerabahuShanmugasundaram,editor,PfizerWorldwide
Research&Development,JürgenBajorath,editor,UniversityofBonn,
01 UniversityofWashington;sponsoredbytheACSDivisionofChemicalInformation.
0
w Description:Washington,DC:AmericanChemicalSociety,[2016]|Series:ACS
2.f symposiumseries:1222|Includesbibliographicalreferencesandindex.
2
12 Identifiers:LCCN2016030299(print)|LCCN2016045731(ebook)|ISBN
6- 9780841231412(alk.paper)|ISBN9780841231405(ebook)
1
20 Subjects:LCSH:Bajorath,Jürgen.|Chemistry--Information
bk- services--Congresses.|Cheminformatics--Congresses.|
21/ Chemistry--Congresses.|HermanSkolnikAward.
0
1 Classification:LCCQD8.3.H472015(print)|LCCQD8.3(ebook)|DDC
0.
1 542/.85--dc23
oi: LCrecordavailableathttps://lccn.loc.gov/2016030299
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5,
ber ThepaperusedinthispublicationmeetstheminimumrequirementsofAmericanNational
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ct Standard for Information Sciences—Permanence of Paper for Printed Library Materials,
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Copyright©2016AmericanChemicalSociety
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Bienstock et al.; Frontiers in Molecular Design and Chemical Information Science - Herman Skolnik Award Symposium 2015: ...
ACS Symposium Series; American Chemical Society: Washington, DC, 2016.
Foreword
The ACS Symposium Series was first published in 1974 to provide a
mechanism for publishing symposia quickly in book form. The purpose of
the series is to publish timely, comprehensive books developed from the ACS
sponsoredsymposiabasedoncurrentscientificresearch. Occasionally,booksare
1 developed from symposia sponsored by other organizations when the topic is of
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2.f
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12 Beforeagreeingtopublishabook,theproposedtableofcontentsisreviewed
16- forappropriateandcomprehensivecoverageandforinteresttotheaudience. Some
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k-2 papersmaybeexcludedtobetterfocusthebook;othersmaybeaddedtoprovide
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1/ comprehensiveness. When appropriate, overview or introductory chapters are
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10 added. Draftsofchaptersarepeer-reviewedpriortofinalacceptanceorrejection,
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1 andmanuscriptsarepreparedincamera-readyformat.
oi:
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6 | As a rule, only original research papers and original review papers are
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0 included in the volumes. Verbatim reproductions of previous published papers
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5, arenotaccepted.
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Bienstock et al.; Frontiers in Molecular Design and Chemical Information Science - Herman Skolnik Award Symposium 2015: ...
ACS Symposium Series; American Chemical Society: Washington, DC, 2016.
Preface
The 2015 Herman Skolnik Award Symposium, held at the 250th National
Meeting of the American Chemical Society in Boston, USA, brought together
well-known investigators from around the world (including the U.S., Europe,
and Asia) who are scientifically active in the broadly defined areas of chemical
1 information science — with special emphasis on chemical informatics — and
0
pr0 computer-aidedmoleculardesign. Presenterscamefromacademiaaswellasthe
22. pharmaceuticalindustry. TheSymposiumwasorganizedwiththestrongsupport
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6-1 of — and chaired by — Dr. Veerabahu Shanmugasundaram, whose invaluable
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0 contributionsmadeitareality.
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k- The chosen theme of the Symposium was “Pioneers, Peers, and the Next
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21/ Generation.”Accordingly,speakerswereselectedtoreflectthescientificevolution
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0.1 of the field (to the extent possible) and included: senior investigators whose
1
oi: pioneeringcontributionshaveshapedchemicalinformatics;othercurrentleaders
6 | d inthefield;andoutstandingjuniorinvestigatorstowhomthetorchwillbepassed
1 oninthefuture. Thelattergroupexclusivelyconsistedofformerstudentsofmine
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5, whoIhadtakenlibertytoselect(whichwas—Iwouldhope—theonlyselfish
er actonthisoccasion),althoughmanyotherswouldhavedeservedtobeinvited.
b
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ct This book has resulted from the 2015 Herman Skolnik Award Symposium.
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b): Without an exception, all presenters agreed to contribute — and did follow
We through, yielding a total of 15 scientific chapters covering a wide spectrum of
e ( topics,including: anhistoricalaccount,keydevelopments,practicalapplications,
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D and novel computational methodologies. As put forward by Dr. Rachelle J.
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c Symposium, it is also hoped that this book might set the stage for subsequent
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Pu ACS book publications covering future Herman Skolnik Award Symposia. Dr,
Bienstock also provided an introductory chapter summarizing the scientific
contributionsincontext.
Firstandforemost,Iwouldliketothankallinvitedspeakersformakingthe
Symposiumamemorableeventandfortheirgreatcontributionstothisbook. In
addition,specialthanksgotomyco-editorsaswellastoArleneFurmanofACS
Booksforherexcellenteditorialhelpandtechnicalsupportinpreparingthisbook.
Wesincerelyhopethatthereadersmightenjoyitasmuchaswedo.
JürgenBajorath
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Bienstock et al.; Frontiers in Molecular Design and Chemical Information Science - Herman Skolnik Award Symposium 2015: ...
ACS Symposium Series; American Chemical Society: Washington, DC, 2016.
RachelleJ.Bienstock
RJBComputationalModelingLLC
ChapelHill, NC27514
VeerabahuShanmugasundaram
CenterofChemistryInnovation&Excellence,WorldWideMedicinalChemistry
PfizerWorldwideResearch&Development
Groton, CT06340
JürgenBajorath
DepartmentofLifeScienceInformatics,B-IT
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00 UniversityofBonn
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2. Bonn53113,Germany
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Bienstock et al.; Frontiers in Molecular Design and Chemical Information Science - Herman Skolnik Award Symposium 2015: ...
ACS Symposium Series; American Chemical Society: Washington, DC, 2016.
Chapter 1
Frontiers in Molecular Design and Chemical
Information Science: Introduction
Rachelle J. Bienstock
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00 RJBComputationalModelingLLC,300PitchPineLane,ChapelHill,
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2.c NorthCarolina27514
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2 *E-mail: [email protected]
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2
0 This introductory chapter is an overview of the material
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10. presentedinthisvolumeandattheACSDivisionofChemical
oi: Information (CINF), Herman Skolnik Award Symposium,
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6 | held in Boston at the ACS National Meeting in Fall 2015.
1
20 Dr. Jurgen Bajorath was the awardee for his contributions in
er 5, the areas of molecular fingerprinting and similarity analysis,
ob virtualscreeningmethodologies, QSAR,andvisualizationand
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b): of these methods to drug discovery. The symposium included
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presentations covering these topical areas, and this volume
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This book is a collection of papers based on a series of talks presented as
a tribute to Dr. Jürgen Bajorath at the ACS Division of Chemical Information
(CINF),HermanSkolnikAwardSymposium,Fall2015,inBoston. TheSkolnik
Award, presented by the division at every fall national ACS meeting, was
establishedtorecognizeoutstandingcontributionsrelatedtothefieldsofchemical
information,andcheminformaticsandisnamedinhonorofDr. HermanSkolnik,
the first awardee (1976). A complete list of awardees can be found on the ACS
CINFdivisionwebsite(http://www.acscinf.org/content/herman-skolnik-award).
Dr. Bajorath is a world leader in the development and application of
cheminformatics and computational solutions to research problems in medicinal
chemistry, chemical biology and life sciences and has done pioneering work
©2016AmericanChemicalSociety
Bienstock et al.; Frontiers in Molecular Design and Chemical Information Science - Herman Skolnik Award Symposium 2015: ...
ACS Symposium Series; American Chemical Society: Washington, DC, 2016.
in the area of BIG DATA analysis in chemistry. He is widely recognized
for his seminal and prolific research work in molecular similarity analysis
and ligand-based virtual screening, fingerprint engineering and application of
advanced machine learning techniques, application of information theoretic
concepts to cheminformatics, large-scale graphical analysis and visualization of
structure-activity relationships, BIG DATA analysis in chemistry and evaluating
SAR content in medicinal chemistry project progression in novel ways. The
Herman Skolnik award was given to Dr. Bajorath in recognition of his seminal
contributionsinthefield.
Dr. Bajorath obtained M.S. and Ph.D. degrees from the Free University,
West–Berlin(PhDadviserWolframSaenger)andworkedinthepharmaceutical
industry in the U.S. at Bristol Myers Squibb the biotech industry (AMRI), and
academia, prior to returning to an appointment as Full Professor and Chair of
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00 LifeScienceInformaticsattheUniversityofBonn,Germany. Hehascontinued
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2.c associations and appointments as Affiliate Professor with The University of
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2 Washington (U.S.), and Guest Professor at University of Strasbourg (France) .
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16- Dr. BajorathcurrentlyservesasanAssociateEditoroftheJournalofMedicinal
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k-2 Chemistryandhasservedontheeditorialboardofseveralmajorresearchjournals.
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1/ The speakers, selected by Dr. Bajorath, and whose talks are represented
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0 amongthechaptersinthisvolume,mostlyrepresentcoworkersandcollaborators
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10. with whom Dr. Bajorath has worked throughout his career. Some were his
oi: mentors,somehispeersandcollaboratorsandsomehisformerstudents.
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6 | The computational and cheminformatics methods discussed, and their
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20 application to drug discovery, are essential for sustaining a viable drug
er 5, development pipeline. It is increasingly challenging to identify new chemical
ob entitiesandtheamountofmoneyandtimeinvestedinresearchtodevelopanew
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O drug has greatly increased over the past 50 years. Joseph A. DiMasi, Director
b): of Economic Analysis, The Tufts Center for the study of Drug Development
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(1),reportedin2014thatR&DExpendituresfortheNewDrugsandBiologics
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at has increased to roughly $50 billion dollars (2013), while the number of new
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Pu Theaveragetimetotakeadrugfromclinicaltestingtoapprovaliscurrently
7.2years. Therefore,theneedtodeveloppredictivecomputationaltechniquesto
driveresearchmoreefficientlytoidentifycompoundsandmolecules,whichhave
thegreatestlikelihoodofbeingdevelopedintosuccessfuldrugsforatarget,isof
greatsignificance.
New methods such as high throughput screening (HTS) and techniques
for the computational analysis of hits have contributed to improvements in
drug discovery efficiency. Millions of compounds can be routinely screened in
bioassays to identify active lead compounds. New types of HTS libraries can
be designed. Often specific compound libraries are used, instead of chemically
diverse libraries, when there is prior knowledge regarding active compounds.
Oftenfragmentlibrariesareusedtoincreasediversityandcoverageofchemical
space,andsometimesleadcompoundsareidentifiedfromnaturalproductinspired
compoundlibraries.
2
Bienstock et al.; Frontiers in Molecular Design and Chemical Information Science - Herman Skolnik Award Symposium 2015: ...
ACS Symposium Series; American Chemical Society: Washington, DC, 2016.
Computational methods such as SAR (Structure-Activity Relationships)
analysis, identifying scaffold classes, clustering using molecular descriptors
and in-silico ADME (Absorption, Distribution, Metabolism, and Excretion)
properties, and fingerprint similarity are all standard in aiding the modern drug
discoveryprocess. Thenovelwaystovisualizeanddisplaychemicalinformation
data and the use of graph theory to display scaffold-based target selective
networks presented in this volume provide for informed analysis of molecules
and structure-activity relationship information. Novel SAR visualization and
analysismethodsincludeheterogeneousSARanalysis,employingactivityversus
selectivity cliffs, SAR monitoring using activity cliffs, and using SAR matrices
basedoncompoundneighborhoods.
Specialized databases developed also play an important role in assisting
new cheminformatics for drug development. PharmMapper DB is a database of
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00 pharmacophores based on solved protein-ligand structures and PharmMapper
h
2.c also provides a web service that aligns pharmacophores associated with specific
2
2 targets. Other drug-target interaction databases available include: STITCH,
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16- Drug2Gene,PROMISCUOUS,DrugBank,ChEMBL,BindingDBandPubChem
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k-2 Bioassay.
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1/ Often nonlinear dimensionality reduction techniques such as SOMs
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0 (Self-Organizing Maps), or PCA (Principal Component Analysis) are applied
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10. to complex high dimensional data to simplify interpretation of the data.
oi: Molecular descriptors are calculated that characterize physical properties, such
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6 | as lipophilicity and electronic properties or ionization potential. 2D descriptors
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20 are based on molecular graphs and account for a variety of topological or
er 5, chemicalfeaturesand3Ddescriptorsincludemolecularconformation-dependent
ob characteristicssuchasmolecularvolumeandshape. Avarietyofthesemethods
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O andtheirapplicationswerepresentedatthissymposium.
b): In this symposium volume, Dr. W. Patrick Walters (Vertex) discusses the
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HTSVisualizertoolinusefordrugdiscoveryatVertex. Highthroughputvirtual
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at screeninghasbeenaninvaluablemethodappliedinmodernpharmaceuticsforhit
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n identification in new drug discovery. It has been used to decide which series of
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bli challengestodrugdiscoveryinpharmaceuticalcompaniessincelibrariescontain
Pu millionsofcompoundsandassociatedbioassaydata. Hitprioritizationisalsoan
issue. Moleculardescriptorsareoftenusedforclusteringcompoundstoanalyze
the data, and cluster threshold can be critical. This approach is based upon
conventionalmolecularframeworks(scaffolds). TheHTSVisualizermethoduses
ring scaffolds and relies on the examination of scaffold frequency. Fingerprint
similaritycanalsobeusedtocompareandsortscaffolds. Scaffoldscanthenbe
associated with activity data to produce SARs. Histograms, density plots, box
plots,andviolinplotscanbeusedtocomparedatadistributions,alongwithREOS
(rapideliminationofswill)alertsandPAINS(pan-assayinterferencecompounds)
filters. Promiscuity plots can be used to cluster on and off target compounds
and ADME assays to classify compounds into good, fair and poor categories.
A successful drug design workflow partitions actives into scaffold classes, and
profileclassesandthencorrelatestheseclasseswithSARandADMEproperties
and prioritizes scaffolds. Vertex uses substructure searches linked to Scifinder
3
Bienstock et al.; Frontiers in Molecular Design and Chemical Information Science - Herman Skolnik Award Symposium 2015: ...
ACS Symposium Series; American Chemical Society: Washington, DC, 2016.
