Lead-Seeking Approaches

224 Pages·2010·4.144 MB·English

by  Kevin D. Freeman-Cook, Daniel W. Kung (auth.), Matthew M. Hayward (eds.)

05
TOPICS IN
MEDICINAL CHEMISTRY
Volume Editor
Matthew M. Hayward
Lead-Seeking
Approaches
123
5
Topics in Medicinal Chemistry
Editorial Board:
P. R.Bernstein ·A. Buschauer ·G.J. Georg ·J. A.Lowe ·H.U.Stilz
Lead-Seeking Approaches
Volume Editor: Matthew M. Hayward
With contributions by
(cid:1) (cid:1) (cid:1)
J. A. Bikker J. W. Ellingboe K. D. Freeman-Cook
(cid:1) (cid:1) (cid:1) (cid:1)
A. M. Gilbert R. K. Harrison D. W. Kung C. A. Lipinski
(cid:1) (cid:1) (cid:1)
J. E. Morin L. S. Narasimhan J. W. Paslay M. Pellecchia
Editor
Dr.MatthewM.Hayward
PfizerGlobalResearch&Development
Dept.NeuroscienceChemistry
EasternPointRd.
GrotonCT06340
MS8220/4339
USA
matt.m.hayward@pfizer.com
ISSN1862-2461 e-ISSN1862-247X
ISBN978-3-642-01074-3 e-ISBN978-3-642-01075-0
DOI10.1007/978-3-642-01075-0
SpringerHeidelbergDordrechtLondonNewYork
LibraryofCongressControlNumber: 2009935068
#Springer-VerlagBerlinHeidelberg2010
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Volume Editors
Dr.MatthewM.Hayward
PfizerGlobalResearch&Development
Dept.NeuroscienceChemistry
EasternPointRd.
GrotonCT06340
MS8220/4339
USA
matt.m.hayward@pfizer.com
Editorial Board
Dr.PeterR.Bernstein JohnA.Lowe
AstraZenecaPharmaceuticals [email protected]
1800ConcordPike
FairfaxResearchCenterB313 Dr.HansUlrichStilz
POBox15437
AventisPharmaDeutschlandGmbH
Wilmington,DE19850-5437
Geb.G838
USA
65926Frankfurta.M.
Germany
Prof.Dr.ArminBuschauer
InstituteofPharmacy
UniversityofRegensburg
Universita¨tsstr.31
93053Regensburg
Germany
Prof.Dr.GundaJ.Georg
UniversityofMinnesota
DepartmentofMedicalChemistry
8-101AWeaverDensfordHall
Minneapolis,MN55455
USA
v
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Aims and Scope
Drug research requires interdisciplinary team-work at the interface between
chemistry,biologyandmedicine.Therefore,thenewtopic-relatedseriesTopics
in Medicinal Chemistry will cover all relevant aspects of drug research, e.g.
pathobiochemistryofdiseases,identificationandvalidationof(emerging)drug
targets, structural biology, drugability of targets, drug design approaches,
chemogenomics, synthetic chemistry including combinatorial methods, bio-
organicchemistry,naturalcompounds,high-throughputscreening,pharmaco-
logical in vitro and in vivo investigations, drug-receptor interactions on the
molecularlevel,structure-activityrelationships,drugabsorption,distribution,
metabolism,elimination,toxicologyandpharmacogenomics.
Ingeneral,specialvolumesareeditedbywellknownguesteditors.
InreferencesTopicsinMedicinalChemistryisabbreviatedTopMedChem
andiscitedasajournal.
vii
Preface to the Series
Medicinal chemistryisbothscienceandart. Thescienceof medicinal chemistry
offersmankindoneofitsbesthopesforimprovingthequalityoflife.Theart
ofmedicinalchemistrycontinuestochallengeitspractitionerswiththeneed
for both intuition and experience to discover new drugs. Hence sharing the
experience of drug discovery is uniquely beneficial to the field of medicinal
chemistry.
TheseriesTopicsinMedicinalChemistryisdesignedtohelpbothnovice
and experienced medicinal chemists share insights from the drug discovery
process. For the novice, the introductory chapter to each volume provides
background and valuable perspective on a field of medicinal chemistry not
availableelsewhere.Succeedingchaptersthenprovideexamplesofsuccessful
drugdiscoveryeffortsthatdescribethemostup-to-dateworkfromthisfield.
Theeditorshavechosentopicsfrombothimportanttherapeuticareasand
fromworkthatadvancesthedisciplineofmedicinalchemistry.Forexample,
cancer, metabolic syndrome and Alzheimer’s disease are fields in which
academia and industry are heavily invested to discover new drugs because
of their considerable unmet medical need. The editors have therefore prior-
itized covering new developments in medicinal chemistry in these fields. In
addition,importantadvancesinthediscipline,suchasfragment-baseddrug
designandotheraspectsofnewlead-seekingapproaches,arealsoplannedfor
earlyvolumesinthisseries.Eachvolumethusoffersauniqueopportunityto
capturethemostup-to-dateperspectiveinanareaofmedicinalchemistry.
Dr.PeterR.Bernstein
Prof.Dr.ArminBuschauer
Prof.Dr.GundaJ.Georg
Dr.JohnLowe
Dr.HansUlrichStilz
ix
Preface to Volume 5
The journey of a drug from conception to launch is a long road, fraught
withmanydetoursanddeadends.Compoundattritioniscausedbyamyriad
of sources, including suboptimal safety, potency and/or PK/PD. In the last
decade,theindustryhasstartedfocusingmoreontheidentificationofquality
lead matter that possesses a multidimensional package of attractive proper-
ties rather than advancing hits solely on potency. Hits with lead quality
attributes and devoid of potential toxic pharmacophores advance faster
throughthediscoverypipelineandstandabetteroverallchanceofsuccess.
Inthis volume we examine how hitsare typicallyidentified and validated
inthepharmaceuticalfieldandhowthischemicalmatterisadvancedtolead
stage. The introductory chapter by Chris Lipinski is a commentary on the
role of medicinal chemists in this process, based on his long and successful
career in the industry. The following three chapters speak of hit identifica-
tion using traditional high throughput screening techniques (Paslay, Morin
andHarrison),virtualscreening(NarasimhanandBikker)andNMRscreen-
ing techniques (Pellecchia). The final two chapters describe the hit triage
(Freeman-Cook and Kung) and the follow-up processes (Ellingboe and
Gilbert)foradvancinghitsintoleads.
The objective of this volume is to provide an overview of the hit-to-lead
process; it is not intended to be all inclusive. Furthermore, much of the
methodology described hereis influenced by the culture of the authors’ res-
pective institutions. In general, however, lead seeking approaches across
industry (and academia) are more similar than they are different and are,
forthemostpart,capturedinthisvolume.
Iamindebtedtotheauthorsfortheircontributionstothisvolume.From
each of their respective chapters I have learned something new, unexpected
andpertinenttomyowncareerindrugdiscovery.Iamalsoindebtedtothe
many readers here at Pfizer who contributed a commentary on the chapters
andhelpedtoinfluencethefinalversionpresentedhere.
July2009 MatthewM.Hayward
xi
Contents
OverviewofHittoLead:TheMedicinalChemist’sRolefromHTS
RetesttoLeadOptimizationHandOff ...................................... 1
ChristopherA.Lipinski
HighThroughputScreeningintheTwenty-FirstCentury ................ 25
JeffW.Paslay,JohnE.Morin,andRichardK.Harrison
LeadDiscoveryUsingVirtualScreening ................................... 85
JackAndrewBikkerandLakshmiS.Narasimhan
NMRSpectroscopyinFragmentBasedDrugDesign ................... 125
MaurizioPellecchia
HitTriage:MedicinalChemistryStrategiestoImprovetheOdds
ofSuccessinDiscovery ................................................... 141
KevinD.Freeman-CookandDanielW.Kung
LeadIdentification ........................................................ 175
JohnW.EllingboeandAdamM.Gilbert
Index ....................................................................... 213
xiii
TopMedChem(2009)5:1–24
DOI:10.1007/7355_2009_4
#Springer‐VerlagBerlinHeidelberg2009
Publishedonline:30June2009
Overview of Hit to Lead: The Medicinal
Chemist’s Role from HTS Retest to Lead
Optimization Hand Off
ChristopherA.Lipinski
Abstract Amedicinalchemistcombinesorganicsynthesisexpertiseandtheability
to optimize chemistry structure–activity relationships (SAR) based on relevant
biomedical information so as to achieve project goals. The ability to optimize
chemistry SAR consists of both the easier to explain logical stepwise structural
modificationthatisoftendescribedbyquantitativestructure–activityrelationships
(QSAR)andthemoredifficulttoexplainexerciseofhigh-orderpatternrecognition.
OptimizingSARisfulloftrapsfortheunwary.Whataretheprosandconsofvarious
types of screens? Should one believe the screening data? How does one optimize
against multiple sometimes conflicting properties? What types of compounds are
worthscreening?Howdoesonejudgethequalityofascreeninghit?Veryimpor-
tantly,drugdiscoveryisateamexerciseinwhichthemedicinalchemistplaysakey
facilitatingrole.Givengoodinterpersonalskills,themedicinalchemist’strainingis
broadenough toenablecooperativeinteractionsacross thewhole discoveryteam.
Chemistry pattern recognition is the unique skill that the medicinal chemist con-
tributes to drug discovery. The ability to relate chemistry structure to biological
activityandtochangechemistrystructuresoastochangeavarietyofbiomedical
parametersinadesireddirectionleadstothesuccessful‘‘drughunter.’’
Keywords HTS,Hittolead,Medicinalchemistry,Patternrecognition,Screening
Contents
1 Introduction:WhatisaMedicinalChemist? ................................................. 3
1.1 TheMedicinalChemist’sRole ......................................................... 4
2 DrugDiscovery,DruggabilityandDevelopability ........................................... 5
2.1 HighThroughputScreening ............................................................ 6
2.2 PhenotypicScreening ................................................................... 6
2.3 FragmentScreening ..................................................................... 8
C.A.Lipinski(*)
ScientificAdvisor,MeliorDiscovery,10ConnshireDrive,Waterford,CT06385-4122,USA
e-mail:[email protected]
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