Integrated drug discovery technologies

561 Pages·2002·7.407 MB·English

by  Houng-Yau Mei, Anthony W Czarnik

Integrated Drug
Discovery
Technologies
edited by
Houng-yau Mei
Rubicon Genomics, Inc.
Ann Arbor, Michigan
Anthony W. Czarnik
Sensors for Medicine and Science, Inc.
Germantown, Maryland
MARCEL
-
MARCEDL EKKERIN, C. NEWY ORK BASEL
DEKKER
Copyright ©2002 by Marcel Dekker,Inc. All Rights Reserved.
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Preface
We scientists in the drug discovery business are not so different from alchemists
of old: “Convert this lead into gold and I shall share my wealth with you.” Or
perhaps, “Convert this lead into gold or else!”You’ve no doubt felt motivation
from both the carrot and the stick during your career,but it probably sounded more
like this: “If you can make a better COX-2 inhibitor, the company’s stock will
triple!” Or, “If we don’t fill our pipeline quickly, someone is going to buy us!”
Whether then or now,the risk/reward ratio is literally a step function,not a con-
tinuum, dependent on a scientist accomplishing a mission his analytical con-
science cannot guarantee.
Now,as in earlier times,we try anything that makes sense in the discovery
process. Because no one method has provided a “lock”on discovery,scientists have
room for style and intuition. “I know the value of computer-aided drug design.”
“The more times you’re up at bat,the more often you’ll hit a home run— so screen.”
“Drug discovery requires a genomic/proteomic/metabolic pathway approach.”
“Start with someone else’s drug and synthesize around the patent.”Who’s right? It
begins to sound like a debate of the merits of one religion versus another. But sci-
ence is about quantitation; why can’t we simply calculate which approach is the
best? Perhaps because no one does “outcomes research” on the drug discovery
process. I think instead it is because science is ultimately a human endeavor,and
each person espousing a discovery philosophy is motivated to make that choice
look like the right one. In the marketplace of ideas,steak sells,and sizzle sells.
Copyright ©2002 by Marcel Dekker,Inc. All Rights Reserved.
This book is about steak. If you hear a little sizzle as well,it’s because the
authors believe passionately in their technology and the philosophy that accom-
panies it. “Lead into gold,” each plaintively wails. Lead, gold, carrots, sticks,
steak,sizzle,and drugs. Let the games begin.
Anthony W. Czarnik
Copyright ©2002 by Marcel Dekker,Inc. All Rights Reserved.
Contents
Preface
Contributors
INTRODUCTION
1. The Motivation:A Top-Down View
Wendell Wierenga
PART I. FROM GENE TO SCREEN
2. Target Identification and Validation:Coupling Genotype
to Phenotype
Gary McMaster
3. Functional Genomics
David O’Hagan
4. Integrated Proteomics Technologies
Joseph A. Loo,James A. Blackledge,Ping Du,Greg W. Kilby,
Robert A. Lepley,Joseph Macri,Rachel R. Ogorzalek Loo,
Stephen T. Rapundalo,and Tracy I. Stevenson
Copyright ©2002 by Marcel Dekker,Inc. All Rights Reserved.
5. Where Science Meets Silicon:Microfabrication Techniques
and Their Scientific Applications
Tony J. Beugelsdijk
6. SNP Scoring for Drug Discovery Applications
John P. Nolan,P. Scott White,and Hong Cai
7. Protein Display Chips
Tina S. Morris
8. Integrated Proteomics Technologies and In Vivo Validation
of Molecular Targets
Christian Rohlff
PART II. HIGH-THROUGHPUT SCREENING
9. High-Throughput Screening as a Discovery Resource
John P. Devlin
10. Fluorescence Correlation Spectroscopy (FCS) and FCS-Related
Confocal Fluorimetric Methods (FCS+plus):Multiple Read-Out
Options for Miniaturized Screening
Cornelia Rufenach,Andreas Scheel,Sylvia Sterrer,
and Rodney Turner
11. Homogeneous Time-Resolved Fluorescence
Loraine V. Upham,Jocelyn W. Burke,Betty Howard,
and Gerard Mathis
12. ADME-Tox Screening in Drug Discovery
Albert P. Li
13. Screening Lead Compounds in the Postgenomic Era:
An Integrated Approach to Knowledge Building
from Living Cells
Kenneth A. Giuliano,Ravi Kapur,Keith R. Olson,
Chandrasekaran Vasudevan,Jian Wang,and Elizabeth S. Woo
14. Miniaturization Technologies for High-Throughput Biology
Walter D. Niles and Peter J. Coassin
Copyright ©2002 by Marcel Dekker,Inc. All Rights Reserved.
15. Data Management for High-Throughput Screening
Lee Amon
PART III. HIGH-THROUGHPUT CHEMISTRY
16. Combinatorial Chemistry:The History and the Basics
Michal Lebl
17. New Synthetic Methodologies
Tasir S. Haque,Andrew P. Combs,and Lorin A. Thompson
18. Supports for Solid-Phase Synthesis
Christophe Fromont,Vincent Pomel,and Mark Bradley
19. The NMR “Toolkit”for Compound Characterization
Paul A. Keifer
20. Materials Management
David A. Kniaz
Copyright ©2002 by Marcel Dekker,Inc. All Rights Reserved.
Contributors
Lee Amon MarketQwest Associates,Fremont,California
Tony J. Beugelsdijk, Ph.D. Los Alamos National Laboratory, Los Alamos,
New Mexico
James A. Blackledge Department of Discovery Technologies, Pfizer Global
Research and Development,Ann Arbor,Michigan
Mark Bradley, Ph.D. Department of Chemistry, University of Southampton,
Southampton,United Kingdom
Jocelyn W. Burke, Ph.D. Department of BioChipventures, Packard Bio-
Science,Meriden,Connecticut
Hong Cai BioScience Division,Los Alamos National Laboratory,Los Alamos,
New Mexico
Peter J. Coassin Department of Instrumentation Research and Development,
Aurora Biosciences Corporation,San Diego,California
Andrew P. Combs, Ph.D. Directed Parallel Synthesis Group, Bristol-Myers
Squibb Company,Wilmington,Delaware
Copyright ©2002 by Marcel Dekker,Inc. All Rights Reserved.
x Contributors
Anthony W. Czarnik,Ph.D. Chief Scientific Officer,Sensors for Medicine and
Science,Inc.,Germantown,Maryland
John P. Devlin, Ph.D. MicroSource Discovery Systems, Inc., Gaylordsville,
Connecticut
Ping Du Department of Discovery Technologies, Pfizer Global Research and
Development,Ann Arbor,Michigan
Christophe Fromont,Ph.D. Ribo Targets Ltd.,Cambridge,United Kingdom
Kenneth A. Giuliano, Ph.D. Department of Assay Development, Cellomics,
Inc.,Pittsburgh,Pennsylvania
Tasir S. Haque, Ph.D. Directed Parallel Synthesis Group, Bristol-Myers
Squibb Company,Wilmington,Delaware
Betty Howard, M.S. Microplate Detection Systems, Packard BioScience,
Downers Grove,Illinois
Ravi Kapur, Ph.D. CellChip Department, Cellomics, Inc., Pittsburgh,
Pennsylvania
Paul A. Keifer,Ph.D. CST Associates,Omaha,Nebraska
Greg W. Kilby Department of Discovery Technologies,Pfizer Global Research
and Development,Ann Arbor,Michigan
David A. Kniaz, B.S., M.B.A. Product Development, SciQuest Inc., Newton
Square,Pennsylvania
Michal Lebl, Ph.D., D.Sc. High Throughput Synthesis Department, Illumina,
Inc.,San Diego,California
Robert A. Lepley, Ph.D.* Department of Discovery Technologies, Pfizer
Global Research and Development,Ann Arbor,Michigan
Albert P. Li,Ph.D. In Vitro Technologies,Inc.,Baltimore,Maryland
Joseph A. Loo, Ph.D. Department of Discovery Technologies, Pfizer Global
Research and Development,Ann Arbor,Michigan
*Current affiliation:TIS Group,Minneapolis,Minnesota
Copyright ©2002 by Marcel Dekker,Inc. All Rights Reserved.