Annual Reports in Combinatorial Chemistry and Molecular Diversity Volume 1 (Annual Reports in Combinatorial Chemistry & Molecular Diversity)

369 Pages·1997·4.38 MB·English

by  W.H. Moos

Annual Reports
in
Combinatorial Chemistry
and
Molecular Diversity
Volume 1
This page intentionally left blank
Annual Reports
in
Combinatorial Chemistry
and
Molecular Diversity
Volume 1
edited by
W.H. Moos
MitoKor
SanDiego,CA92121,U.S.A.
M.R. Pavia
Sphinx Pharmaceuticals
Cambridge, MA 02139, U.S.A.
B.K. Kay
University of North Carolina
Chapel Hill, NC 27599-3280, U.S.A.
A.D. Ellington
IndianaUniversity
Bloomington, IN 47405, U.S.A.
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Preface
Combinatorial chemistry and molecular diversity approaches to scientific inquiry and
novel product research and development (R&D) have exploded in the 1990s. For example,
in the preparation of drug candidates, the automated, permutational, and combinatorial
useofchemicalbuildingblocksnowallowsthegenerationandscreeningofunprecedented
numbers of compounds. Drug discovery – better, faster, cheaper! Notably, more com-
pounds have been made and screened in the 1990s than in the last 100 years ofpharma-
ceutical research combined, and new drug candidates are possibly for the first time mak-
ingtheirwayintoclinical developmentpipelines in amore efficientway.
Afterleadingthewayin 1995–1996withthefirstscientificjournaltorepresentthisnew
field and discipline, ESCOM leads the way again with ‘Annual Reports in Combinatorial
Chemistry and Molecular Diversity’ (ARCCMD). Just as ‘Annual Reports in Medicinal
Chemistry’ (Academic Press) has established a premier position for yearly reviews in
pharmaceuticalchemistryandrelatedtopics,ARCCMDwilldothe samefortheburgeon-
ingnew arena ofcombinatorialchemistry andmoleculardiversity. This annual is a ‘must
read’foreveryoneinvolvedinpharmaceuticalandbiotechnologyR&D, andalsoforthose
who are training students for careers in the industry. Moreover, as the field of molecular
diversity expands into areas such as bio-organic chemistry, materials science, and beyond,
theserieswillbeofconsiderablebenefitto readerswho workat state-of-the-art interfaces
of science and technology.
This first volume in the series pulls together authors from the U.S., Europe, and the
Pacific Rim. Coedited by Michael Pavia (Lilly-Sphinx), Brian Kay (University ofNorth
Carolina), Andy Ellington (Indiana University), and Walter Moos (MitoKor), it covers
three major areas: (i) combinatorial chemistry; (ii) combinatorial biology and evolution;
and (iii)informatics and related topics. Within each section, chaptershavebeenprepared
by experts in the field. The first section covers: mixture pools versus parallel individual
compound synthesis, solution versus solid-phase synthesis and solid supports, analytical
tools, automation, and small-molecule libraries. The second section includes: theoretical
issues, phage display, synthetic peptide libraries, and nucleic acid libraries. The third and
final section includes: databases and library design, high throughput screening, coding
strategies versus deconvolutions, intellectual property issues, deals and collaborations,
successes to date, and a compendium of solid-phase chemistry publications.
We hope you enjoy this new annual forum!
Walter Moos
Michael Pavia
Brian Kay
Andy Ellington
V
Contents
Preface v
Section I: Combinatorial Chemistry
Combinatorial chemistry: A perspective 3
M.R. Pavia (SphinxPharmaceuticals, Cambridge, MA. U.S.A.)
Techniques for mixture synthesis
J.S. Kiely (HoughtenPharmaceuticalsInc.,SanDiego, CA, U.S.A)
Introduction 6
Methods for the preparation of mixture-based libraries 6
Iterative library deconvolutions 7
Heterocycliclibraries 7
Peptidomimetic, peptide and receptor libraries 9
Newer deconvolution methods and expansions oflibrary diversity 10
Rationale for mixture-based combinatorial libraries 15
Conclusions 16
Techniques for single-compound synthesis
S.SarsharandA.M.M.Mjalli(OntogenCorp.,Carlsbad,CA,U.S.A)
Issuestoconsider 19
Spatiallydispersed strategy 20
The Multipin SPOC system 22
The DIVERSOMER method 23
The OntoBLOCK system 23
Split and recombine strategy 25
Comparison oftechniques 27
Conclusions and future prospects 28
Recent advances in solid-phase synthesis
S.E. Hall (SphinxPharmaceuticals,Durham,NC, U.S.A.)
Introduction 30
Solid-phasechemistry 30
Cleavagemethodology 30
Reactions 30
Solid-phase-supported reagents and scavengers 36
Conclusions 39
vi
Contents
Selection of supports for solid-phase organic synthesis
I. Sucholeiki (Sphinx Pharmaceuticals, Cambridge,MA,U.S.A)
Introduction 41
Monitoring the solid support 41
Types ofsupports 42
Kieselguhr-polyacrylamide composite 42
Polystyrene-polyacrylamidecomposite 43
Polystyrene-polyethyleneglycolcomposite 43
Polyethyleneglycol-polyacrylamidecomposite(PEGA) 43
Controlled pore glass (CPG) 43
Kieselguhr 43
Polyethylene-basedsupports 43
Cellulose-based supports 44
The effect ofthe support on the rate ofsolid-phase reactions 44
Enhancing support loadings 45
Summary and Conclusions 47
Solution-phase combinatorial chemistry
D.M. Coe and R. Storer (Glaxo WellcomeResearchandDevelopment, Stevenage,UK.)
Introduction 50
Solution-phase synthesis ofpools ofcompounds 51
Solution-phase synthesis ofdiscrete compounds 51
Liquid-phase synthesis 54
Use ofsupported reagents 56
Conclusions 57
Analytical methods for the quality control of combinatorial libraries
W.L. Fitch (Affymax Research Institute, Santa Clara, CA, U.S.A.)
Introduction 59
Analytical methods used in solid-phase synthesis 59
Measuring yields and loading 60
Following reactions and determining structures ofintermediates on-bead 60
Cleave and characterize methods for evaluating intermediates and products 62
Analytical methods for evaluating libraries 64
Parallel synthesis 64
Split/pool solid-phase libraries and solution-phase pools 65
Conclusions 66
Automated synthesis
S.H. DeWitt (DIVERSOMER Technologies Inc. and Parke-Davis Pharmaceutical Research,
Ann Arbor, MI, U.S.A.)
Introduction 69
System designs 69
vii
Contents
Reactors 69
Architecture 70
Valving automation 70
Robotic automation 71
Applications 71
Process optimization 71
Peptide synthesis 72
Organic synthesis and combinatorial chemistry 72
Conclusions 73
Applications of combinatorial technology to drug discovery
D.V. Patel (VersicorInc,,SouthSanFrancisco, CA, U.S.A.)
Introduction 78
Synthesis and screening ofoligomeric peptide and non-peptide libraries 78
Synthesis and screening oforthogonal and binary encoded libraries 80
Combinatorial synthesis and screening ofheterocyclic, drug-like scaffold libraries 81
Parallel synthesis and screening ofbioactive pharmacophore libraries 84
Solid-phase synthesis of heterocyclic, drug-like molecules 86
Conclusions 88
Section II: Combinatorial Biology and Evolution
Combinatorial biology and evolution: A perspective
93
B.K. Kay and A.D. Ellington (University of North Carolina at Chapel Hill, Chapel Hill,
NCandIndianaUniversity,Bloomington,IN U.S.A.)
Models and search strategies for applied molecular evolution
B. Levitan (SantaFeInstitute, SantaFe,NM, U.S.A.)
Introduction 95
Laboratory technique-based models and search strategies 96
Affinity distribution models 96
Comparing methods of molecular search 97
Models and search strategies 99
SELEXION model 99
SELEXION results 101
Mandecki et al. model of phage display 104
Mandecki model results 105
Levitan/Kauffman model of phage display 107
Levitan/Kauffman model results 112
Conclusions from laboratory technique-based models 119
Fitness landscape-based models and search strategies 124
Definitions 124
Sequence space 124
viii
Contents
Othermolecularspaces 125
Fitnesslandscapes 126
Properties offitnesslandscapes 127
Models offitnesslandscapes 128
Spinglass-likemodels 129
RNAsecondary structure models 133
Otherapproaches 134
Library design and search strategies 135
Designing theinitiallibrary 135
Measuringmolecular landscape properties 138
Searchonspinglass-likelandscapes 140
Search on RNA secondary structure landscapes 143
Poolingstrategies 144
Conclusions fromlandscape-basedmodels 147
Conclusions 148
Molecular evolutionary biology
P. Schuster (Institutfür Theoretische ChemieundStrahlenchemieder Universität Wien,
Wien, AustriaandSanta FeInstitute, Santa Fe, NM, U.S.A.)
Introduction 153
Evolutionarydynamics 154
TheRNAmodel 157
Evolutionarybiotechnology 163
Concluding remarksandperspectives 166
Landscapes for molecular evolution: Lessons from in vitro selection
experiments with nucleic acids
S.D. Jhaveri, I. Hirao, S. Bell, K.W. Uphoffand A.D. Ellington
(IndianaUniversity,Bloomington,IN, U.S.A.)
Introduction 169
Invitroselection 169
A cartoon representation oflandscapes that map sequence to function 172
How rugged are landscapes? 174
How does the length ofthe random sequence pool affect the landscape? 178
Is there a tyranny of short motifs? 179
How does nucleic acid chemistry affect the landscape? 181
What effect does the target have onthe landscape? 183
Therelationship between affinityandspecificity 187
Conclusions 190
Synthetic peptide libraries
Z.-G. Zhao and K.S. Lam (The University of Arizona, Tucson, AZ, U.S.A.)
Introduction 192
Peptide chemistry 193
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