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Book Review Handbook of Drug Screening. Edited by Ramakrishna Seethala and Prabhavathi B. Fernandes

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Handbook of Drug Screening
Edited by Ramakrishna Seethala
and Prabhavathi B. Fernandes.
Marcel Dekker,
New York 2001.
648 pp., softcover
$ 195.00.—ISBN
On first looking at this Handbook of
Drug Screening the reader may feel that
a publication with this title would need
to be bigger and thicker to deserve the
“Handbook” description. But from a
first glance at the lists of contents and of
authors it is immediately apparent that
the book has been written by many
experts in this field, including scientists
from different disciplines who are concerned on a daily basis with every aspect
of modern drug research by automated
After a useful preface which gives an
overview and explanation of the book!s
contents, the main text begins with a
short introductory chapter discussing
the main factors that have influenced
the historical development of the search
for new drugs. The following chapter
gives a brief summary of the aspects to
be considered when choosing an assay
method for setting up a high-throughput
screening (HTS) program, a strategy
described here as the evaluation of
hundreds of thousands of substances
within a relatively short time. Briefly,
the criteria are that the assay must be
reproducible, robust, and capable of
being automated, and must be able to
rapidly generate and process vast quantities of data. It must also be costAngew. Chem. Int. Ed. 2003, 42, 3575 – 3577
effective, as measured by the cost per
data point. Thus the requirements for an
HTS assay differ considerably from
those for other types of assays. The
next chapter is entirely devoted to discussing the different types of HTS
assays. The chapter describes the appropriate techniques according to whether
the assay is homogeneous (where the
test substances are pipetted together
and measured), or heterogeneous
(where at least one separation step is
necessary before measurement). A further separate chapter is then devoted to
a very thorough and detailed discussion
of homogeneous assays. This special
attention to homogeneous assays is
appropriate since such an assay best
fulfills the above mentioned aim for a
testing system that is as simple as
possible (and therefore usually rapid
and cheap). Two chapters describe the
use of microorganisms, especially
Escherichia coli and Saccharomyces cerevisiae, as the basis for a screening
system. Also belonging to this class of
techniques and applications is the “yeast
two hybrid” system, which has opened
up a new dimension in the search for
protein – protein interactions.
Four of the following five chapters
are devoted to the main groups of
biological target molecules on which
the pharmaceutical industry is concentrating its search for small-molecule
active agents, namely enzymes, ion
channels, RNA transcription regulators,
and membrane-bound receptors. The
last of these are currently the target
molecules receiving most attention, and
not surprisingly that chapter is the
longest with over 70 pages. At this
point the editors have inserted a short
chapter describing various techniques
for assays using living cells (“functional
assays”), which are especially useful in
HTS programs where the underlying
biological reaction cannot be broken
down into individual components. This
chapter also considers the often
neglected question of which recombinant techniques are most effective for
the expressivity of the target molecules
within or on cells.
The last third of the book consists of
nine chapters, each about 20 pages long,
describing different areas of research
that might be grouped together under
the heading “classical HTS”. Two
ters discuss applications to investigating
the uptake, distribution, metabolism,
and excretion of compounds considered
as potential drugs, and their possible
toxic effects (e.g., to the liver). Two
others are concerned with developments
in automated laboratory instruments
and how these can be incorporated
into the automation of assays. The
opportunities and problems presented
by advances in miniaturization of assay
procedures are also discussed. Three
chapters are devoted to the question of
how the knowledge of the human
genome can be used to help in the
search for new drugs. Here it becomes
clear that the necessary advances in
techniques for investigating RNA
expression (genomics) and protein
expression (proteomics) in cells and
organs (e.g., using animal models or
following treatment with drugs) are in
many respects similar to those for HTS,
as discussed above: miniaturization for
reducing costs, a high level of robustness, and the need to efficiently generate
and process large amounts of data.
It is already evident from Chapter 1
of this book that “screening” has undergone rapid developments. Therefore
one must ask how up-to-date this book
can be, considering that it was published
in 2001 and covers the literature only up
to 1998. It does at least contain all the
well-established general methods, but of
course new equipment or new versions
of that already existing have become
available, and the capabilities of standard equipment have been extended. It
remains to be seen whether the many
different instruments and assay platforms will continue to coexist, and
whether new technologies still to come
will make present methods obsolete.
The book claims to address three
groups of users: scientists who intend to
make a career in “screening”, those who
are interested in finding out about
modern automated methods for discovering new drugs, and those who seek an
assay method for their specific target
molecules. In my opinion all three
groups will be very well served by the
book, as the chapters describe the
various methods concisely but certainly
in sufficient detail (including the biological fundamentals), illustrated by
many diagrams. The book includes a
wealth of examples of applications,
+ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
often accompanied by experimental
data. Commercially available instruments for the measurements are also
listed and briefly described. However,
there is a certain amount of repetition
between individual chapters, and this, as
well as the lack of cross-references,
makes the book difficult reading for
the user who wants only a general
overview of HTS. Both these faults are
undoubtedly the result of the chapters
having been written by different
authors, thus ensuring the highest possible standard of expertise for each area.
The overlapping can also be an advantage from the point of view of the
researcher seeking the best solution for
a particular problem, as it offers the
possibility not only to look for an answer
directly in the relevant chapter but also
to gather as much information as possible. That is certainly something that one
expects from a “handbook”.
Reinhold M ller
Knoll GmbH
Ludwigshafen (Germany)
BioNMR in Drug Research
Edited by Oliver
Zerbe. (Series:
Methods and
Principles in
Medicinal Chemistry, Vol. 16.
Series editors: R.
Mannhold, H.
Kubinyi, G. Folkers.) Wiley-VCH,
Weinheim 2003.
484 pp., hardcover E 149.00.—ISBN
The five main sections into which this
book is divided range from basic techniques through modern methods of
NMR spectroscopy to strategies for
using NMR in drug research and development.
The first section, “Basic Techniques”, consists of chapters on state-ofthe-art methods for the expression of
isotopically enriched proteins, automated methods for structure determi-
nation and molecular calculations, and
new techniques for noise suppression
and for obtaining enhanced NMR sensitivity. With regard to which of these
three areas is most important, the
answer certainly depends on one!s
point of view. All three chapters are
excellent, and each one includes an
extensive bibliography for readers who
need more details. In my view the
chapter on expression of isotopically
enriched proteins is especially informative and valuable from a practical standpoint. It includes tables which present
key information about established and
newer expression systems in a clear and
easily accessible form, enabling one to
quickly grasp the essential features. This
chapter has a central function in the
book because methods for isotopic
enrichment are a very important prerequisite for drug research.
The second section begins with a
concise survey of different strategies for
interpreting protein NMR spectra. That
is followed by a chapter explaining
important details of NMR spectroscopic
investigations, especially as applied to
membrane-associated peptides and proteins, and a chapter on NMR analysis of
nucleic acids. In these chapters special
emphasis is given to current developments in the application of NMR spectroscopy to studies of membrane proteins. The chapter concerned with membrane-associated peptides and proteins,
which is titled “NMR Experiments in
the Area of Drug Design”, is undoubtedly the most exciting of the two, since
this class of biomolecules, while still
presenting difficult problems, also offers
the most interesting targets in the search
for new drugs.
The third section of the book,
“Modern Spectroscopic Techniques”, is
the longest, which is not surprising in
view of the many very interesting new
methods that have been developed in
recent years. The book certainly does
full justice to those developments,
describing in detail techniques such as
cross-correlated relaxation, residual
dipolar couplings, measurements of the
scalar coupling through hydrogen bonds,
the TROSY concept, and measurements
of 15N relaxation parameters. The chapter also includes a paragraph on solidstate MAS-NMR studies of isotopically
enriched biological samples, thus recog-
+ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
nizing the extent to which these techniques have become more widely used in
the last few years.
The last two sections of the book are
titled “Tools for Investigation of Drug –
Receptor Complexes and for Ligand
Screening” and “Strategies for Drug
Development Using NMR”. The many
different aspects covered in these sections include descriptions of techniques,
automated procedures for identifying
hits, and concepts such as the shapes
strategy that are aimed at identifying
lead structures. It is the last of these
areas that is richest in examples of the
application of NMR spectroscopy in
drug design. Also, however, one of the
most important strengths of NMR spectroscopy as an aid to drug design is
shown in a highly informative and
clearly written chapter on “NMR of
Weakly Binding Ligands”. The last
chapter of the book is concerned with
the application of NMR-supported drug
design to very large protein molecules.
The methods described in this chapter
are based on the TROSY experiment,
which links up neatly to the earlier more
theoretical chapters in the book.
The editor, Oliver Zerbe, has managed to recruit a team of well-recognized experts as authors for this book,
thereby ensuring a high standard of (as
they say in the news media) “reliable
and objective reporting”. Bio-NMR in
Drug Research is not only of interest to
specialists in pharmaceutical research
and development, but will certainly also
be a valuable resource for everyone
concerned with the latest methods of
NMR spectroscopy and their applications to biomolecules.
Thomas Peters
Institut f?r Chemie
UniversitAt L?beck (Germany)
Angew. Chem. Int. Ed. 2003, 42, 3575 – 3577
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seethala, drug, fernandez, book, screening, handbook, edited, review, ramakrishna, prabhavathi
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