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Advances in Combinatorial Chemistry &
High Throughput Screening
Volume 1
Editor
Rathnam Chaguturu
Center for A d vanced Dru g R es e ar ch
SRI International
Harrisonburg, VA 22802
USA
Advances in Combinatorial
Chemistry & High Throughput
Screening
Volume 1
ISSN: 2589-2835 (Print)
ISSN: 2214-515X (Online)
ISBN: 978-1-60805-746-7 (Print)
ISBN: 978-1-60805-745-0 (Online)
Year of Publication: 2013
DOI:10.2174/97816080574501130101
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CONTENTS
Foreword i
Preface iii
List of Cont ri b u t ors v
CHAPTERS
1. Assessing Chemicals Using Partial Order Ranking Methodology
Lars Carlse n
3
2. Building a Chemical Space Based on Fragment Descriptors
Igor I. Baskin and Alexandre Varnek
36
3. Fluorescent Probes for Cellular Assays
George T. Hanson and Bonnie J. Hanson
60
4. Label-Free Cell Phenotypic GPCR Drug Discovery
Ye Fang
84
5. Immunological Assays: Biotools for High Throughput Screening
and Characterisation of Combinatorial Libraries
Maria Â. Taipa
130
6. Screening and Mechanism-Based Evaluation of Estrogenic
Botanical Extracts
Cassia R. Overk and Judy L. Bolton
159
7. A Homogeneous Platform to Discover Inhibitors of the GoLoco
Motif/G-alpha Interaction
Adam J. Kimple, Adam Yasgar, Mark Hughes, Ajit Jadhav, Francis
S. Willard, Robin E. Muller, Christopher P. Austin, James Inglese,
Gordon C. Ibeanu, David P. Siderovski and Anton Simeonov
187
Contd…..
8. G-Protein Activation State-Selective Binding Peptides as New
Tools for Probing Heterotrimeric G-protein Subunit Signaling
Dynamics
Christopher A. Johnston, Francis S. Willard, Kevin Ramer,
Rainer Blaesius, Natalia Roques and David P. Siderovski
219
Index 248
i
FOREWORD
Aiming to accelerate the therapeutic interaction of the expanding chemical spa ce
and biological target space to advance drug discovery, this inaugural eBook,
Advances in Combinatorial Chemistry & High Throughput Screening (ACCHTS),
opens up a new avenue for rapid access to a focused collection of highly regarded
contributions in the field. Importantly, ACCHTS not only highlights major
conceptual advances and cutting edge technologies, but also serves as a much-
needed window to the timely, informative, and enabling resources in its parent
journal CCHTS.
Although biological and biomedical advances coupled with genomics studies have
uncovered a large number of potential drug targets, the number of novel target
drugs that enter clinics remains dismally low at about four per year during the past
thirty years. In order to rapidly translate such impressive gains in biomedical
research into much-needed therapeutic agents, we must improve each step in the
drug discovery process. For example, developing bioassays that faithfully reflect
in vivo biological processes is essential. Expanding chemical space through
innovative combinatorial chemistry and natural products-inspired approaches
allows for effective interrogation of high-value targets, such as GPCRs and
kinases, as well as traditionally un-druggable targets, such as protein-protein
interaction interfaces. Progress in laboratory automation and highly sensitive and
versatile detection technologies enables unprecedented high throughput screening
operations in both industry and academia to accelerate the process of drug lead
discovery and characterization. Chapters selected f or this inaugural volume ref lect
promising developments in these critical areas. These contributions describe
innovative assay platforms that include both cell-based phenotypic assays and
biochemical assays for efficient HTS, and chemical methodologies for building
and assessing chemicals. I hope that these chapters will set the standard for future
publications to come.
While technology development is important for accelerating the process of drug
discovery, rapid development of the chemical biology field and the emergence of
a large number of chemical probes are expected to fuel innovations that will be
essential for finding novel target drugs. By integrating new developments in
ii
chemical biology and probe discovery into drug discovery, ACCHTS would be in
a unique position to catalyze the discovery and development of the next
generation of efficacious and safe therapeutic agents.
Haian Fu
Department of Pharmacology
Emory University School of Medicine
Atlanta, GA 30322
USA
iii
PREFACE
There are about 7000 diseases that afflict mankin d, treatments are available only
for ~200 diseases. With the genetic basis for most of these diseases known, there
is a large repertoire of un-drugged therapeutic targets to explore. T he process of
drug discovery has benefited in the pa st decade by the advent and rise of high-
throughput screening (HTS), an early and vital step of screening small molecule
libraries primarily through biochemical and cell-based assays. Central to every
HTS endeavor is the compound collection. Industry-style probe discovery has
now gained unparalleled momentum with the availability of vendor-supplied
chemical libraries and ready access to institutional HTS labor ator ies. T he US NIH
Roadmap program and the newly organized EU-Open Screen have greatly
influenced the global drug discovery landscap e. Likewise, India and China have
stepped up their drug discovery research infrastructure. The recently formed
International Chemical Biology Society, an independent, nonpr ofit organization,
is dedicating itself to promote research and educational opportunities at the
interface of chemistry and biology, by providing an important international forum
that brings together cross-disciplinary scientists from academia, nonprofit
organizations, government, and industry to com municate new research and help
translate the power of chemical biology to advance human health.
Combinatorial Chemistry & High Throughput Screening (CCHTS) was the only
journal that served the needs of the two disciplines, high throughput screening and
combinatorial chemistry, when the very first issue appeared in 1998. The Aims
and Scope of CCHTS have never been more relevant than now. A look at the
manuscripts published in Combinatorial Chemistry & High Throughput Screening
is reflective of this commitment and readership’s interest. We are making every
effort for the journal’s success, improving its high standard by publishing quality
science articles and guest-edited thematic issues.
This eBook, Advances in Combinatorial Chemistry & High Throughput Screening
(ACCHTS), is another effort to showcase CCHTS authors and a significant
milestone in the annals of CCHTS. The wide range of topics represented by these
chapters is faithful to the scope and purpose of CCHTS, and a testament to
CCHTS contributions in advancing drug discovery on full throttle. In the words of
iv
my good friend, Professor Haian Fu, this eBook “opens up a new avenue for rapid
access to a focused collection of highly regarded contributions in the field.”
My gratitude to all those who have helped in developing ACCHTS, the authors,
reviewers, section editors and publishing staff, for their time, advice, expertise,
and tireless effort.
Rathnam Chaguturu
Center for Advanced Drug Research
SRI International
Harrisonburg, VA 22802
USA
E-mail: rathnam.chaguturu@sri.com
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