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Evaluation of Enzyme Inhibitors in Drug Discovery. By Robert A. Copeland

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Evaluation of Enzyme Inhibitors in
Drug Discovery
By Robert A. Copeland. Wiley-Interscience, Hoboken
2005. 271 pp.,
E 69.90.—ISBN
Modulation of protein function by
interaction with small-molecule inhibitors is central to both chemical biology
(the scientific basis) and the pharmaceutical industry, which turns science
into products of benefit to mankind.
Enzymes are probably the most important class of protein drug targets, owing
to their important roles in life processes
and the fact that enzyme-active sites and
other ligand-binding pockets are ideally
suited for high-affinity interaction with
drugs. Probably every chemist, at least
once during his or her undergraduate
education, learns something about
Michaelis–Menten kinetics, which contains the fundamental equation in enzymology, which describes substrate–
enzyme interaction. But the inhibition
of proteins involves many more aspects
that are less well known and deserve
more attention. Standard biochemistry
textbooks usually fail to teach those subtleties, which anyone dealing with the
interaction between small molecules
and proteins needs to know about. In
his book Evaluation of Enzyme Inhibitors in Drug Discovery, Robert Copeland, whose authority is based on a distinguished career as an enzymologist in
Angew. Chem. Int. Ed. 2005, 44, 6445 – 6446
both industry and academia, provides
an excellent and clearly written work,
which will help many readers to understand this discipline.
In the first two chapters, the author
gives a concise but informative introduction to the fundamental principles of
enzyme catalysis and substrate binding.
Even in these introductory chapters, it
will take the reader only a few paragraphs to appreciate one of the big
strengths of this book: the author generously shares his great experience as an
industrial practitioner, and augments
the theoretical discussion with many
instructive examples in which potential
pitfalls and solutions for frequently
encountered problems are illuminated.
This personal note makes an especially
valuable contribution to the following
chapter, which presents considerations
about assays for the screening of compound libraries.
A major part of this book is dedicated to the reversible modes of inhibitor interactions with enzymes, in which
uncompetitive inhibitors have to be distinguished. The author reminds the
reader that the commonly used IC50
value for the description of inhibitor
efficiency is significantly affected by
the assay conditions, and describes
simple experiments that should be carried out to guarantee a well-designed
assay or to avoid the misinterpretation
of data. Here again, the author achieves
a good balance between an in-depth
kinetic analysis (containing many equations and graphs) and fascinating case
studies of failed or marketed drugs,
which illustrate the theoretical considerations. In the next two chapters, the
mechanistic fundamentals, some practical examples, and the clinical advantages of slow-binding and tight-binding
inhibitors, are discussed thoroughly.
The final chapter discusses irreversible enzyme inactivation and the applications of affinity labels and mechanismbased inactivators as drugs.
As in any book, even this carefully
edited monograph is not free from
errors, but most of these do not distort
the meaning. The index is reasonably
effective for finding particular topics in
the text, but the reader would certainly
have benefited from a list of abbreviations, which is sadly missed when one
makes the effort of working through
the many equations.
In conclusion, Evaluation of Enzyme
Inhibitors in Drug Discovery provides
an excellent introduction to the key
aspects of enzymology, enzyme inhibition, and the development of drugs. It
distinguishes itself from other books by
its balanced discussion of both theory
and experimental practice. In his preface the author modestly describes his
book as a guide for medicinal chemists
and pharmacologists. I think this book
definitely deserves a bigger readership,
and I recommend it to everybody who
is interested in the interaction of proteins with small molecules. Every
chemistry library in academia or industry should own a copy of this book.
Rolf Breinbauer
Max-Planck-Institut f*r
Molekulare Physiologie
and Universit-t Dortmund (Germany)
DOI: 10.1002/anie.200585328
Essential NMR
By Bernhard Blmich. Springer
Verlag, Heidelberg
2005. 243 pp., softcover E 37.50.—
ISBN 3-540-23605-8
In the 60 years that have passed
since the discovery of the phenomenon
of nuclear magnetic resonance (NMR),
the subject has developed enormously,
partly because of the revolution in
microelectronics and computer technology that has taken place during that
time. In addition to the classical applications in chemical analysis, NMR
spectroscopy has made spectacular
advances into many other areas of application, in medical diagnostics, biomedical research, materials characterization,
process technology, quality assurance,
and even geological research.
The author1s aim was to collect these
different areas of application together
within a single book, in a concise and
informative way, so that scientists and
6 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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discovery, drug, enzymes, inhibitors, evaluation, roberts, copeland
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