Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists (Methods of Biochemical Analysis) [Hardcover]

Robert A. Copeland (Author)

Book Description

ISBN-10: 0471686964 | ISBN-13: 978-0471686965 | Publication Date: March 28, 2005 | Edition: 1

Vital information for discovering and optimizing new drugs
"Understanding the data and the experimental details that support it has always been at the heart of good science and the assumption challenging process that leads from good science to drug discovery. This book helps medicinal chemists and pharmacologists to do exactly that in the realm of enzyme inhibitors."
-Paul S. Anderson, PhD
This publication provides readers with a thorough understanding of enzyme-inhibitor evaluation to assist them in their efforts to discover and optimize novel drug therapies. Key topics such as competitive, noncompetitive, and uncompetitive inhibition, slow binding, tight binding, and the use of Hill coefficients to study reaction stoichiometry are all presented. Examples of key concepts are presented with an emphasis on clinical relevance and practical applications.
Targeted to medicinal chemists and pharmacologists, Evaluation of Enzyme Inhibitors in Drug Discovery focuses on the questions that they need to address:
* What opportunities for inhibitor interactions with enzyme targets arise from consideration of the catalytic reaction mechanism?
* How are inhibitors evaluated for potency, selectivity, and mode of action?
* What are the advantages and disadvantages of specific inhibition modalities with respect to efficacy in vivo?
* What information do medicinal chemists and pharmacologists need from their biochemistry and enzymology colleagues to effectively pursue lead optimization?
Beginning with a discussion of the advantages of enzymes as targets for drug discovery, the publication then explores the reaction mechanisms of enzyme catalysis and the types of interactions that can occur between enzymes and inhibitory molecules that lend themselves to therapeutic use. Next are discussions of mechanistic issues that must be considered when designing enzyme assays for compound library screening and for lead optimization efforts. Finally, the publication delves into special forms of inhibition that are commonly encountered in drug discovery efforts, but can be easily overlooked or misinterpreted.
This publication is designed to provide students with a solid foundation in enzymology and its role in drug discovery. Medicinal chemists and pharmacologists can refer to individual chapters as specific issues arise during the course of their ongoing drug discovery efforts.

Editorial Reviews

Review

"...a valuable addition to the library of individual investigators, as well as a must for any reference collection." (Drug Development and Industrial Pharmacy, No. 3, 2006)

"This book serves as an extremely valuable starting point for anyone who needs to acquire/or interpret good kinetic data for enzyme inhibition." (Clinical Chemistry, November 2005)

From the Back Cover

Vital information for discovering and optimizing new drugs

"Understanding the data and the experimental details that support it has always been at the heart of good science and the assumption challenging process that leads from good science to drug discovery. This book helps medicinal chemists and pharmacologists to do exactly that in the realm of enzyme inhibitors."
—Paul S. Anderson, PhD

This publication provides readers with a thorough understanding of enzyme-inhibitor evaluation to assist them in their efforts to discover and optimize novel drug therapies. Key topics such as competitive, noncompetitive, and uncompetitive inhibition, slow binding, tight binding, and the use of Hill coefficients to study reaction stoichiometry are all presented. Examples of key concepts are presented with an emphasis on clinical relevance and practical applications.

Targeted to medicinal chemists and pharmacologists, Evaluation of Enzyme Inhibitors in Drug Discovery focuses on the questions that they need to address:

• What opportunities for inhibitor interactions with enzyme targets arise from consideration of the catalytic reaction mechanism?
• How are inhibitors evaluated for potency, selectivity, and mode of action?
• What are the advantages and disadvantages of specific inhibition modalities with respect to efficacy in vivo?
• What information do medicinal chemists and pharmacologists need from their biochemistry and enzymology colleagues to effectively pursue lead optimization?

Beginning with a discussion of the advantages of enzymes as targets for drug discovery, the publication then explores the reaction mechanisms of enzyme catalysis and the types of interactions that can occur between enzymes and inhibitory molecules that lend themselves to therapeutic use. Next are discussions of mechanistic issues that must be considered when designing enzyme assays for compound library screening and for lead optimization efforts. Finally, the publication delves into special forms of inhibition that are commonly encountered in drug discovery efforts, but can be easily overlooked or misinterpreted.

This publication is designed to provide students with a solid foundation in enzymology and its role in drug discovery. Medicinal chemists and pharmacologists can refer to individual chapters as specific issues arise during the course of their ongoing drug discovery efforts.

See all Editorial Reviews

Product Details

• Hardcover: 300 pages
• Publisher: Wiley-Interscience; 1 edition (March 28, 2005)
• Language: English
• ISBN-10: 0471686964
• ISBN-13: 978-0471686965
• Product Dimensions: 9.3 x 6.2 x 0.7 inches
• Shipping Weight: 1.2 pounds (View shipping rates and policies)
• Average Customer Review: 5.0 out of 5 stars  See all reviews (3 customer reviews)
• Amazon Best Sellers Rank: #649,840 in Books (See Top 100 in Books)

More About the Author

Robert A. Copeland, Ph.D. is Executive Vice President and Chief Scientific Officer at Epizyme, Inc. He joined Epizyme in September, 2008, from GlaxoSmithKline, where he was Vice President, Biology, Oncology Center of Excellence in Drug Discovery. Dr. Copeland is also Adjunct Professor of Biochemistry and Biophysics and a Fellow of the Eldridge Reeves Johnson Foundation at the University of Pennsylvania School of Medicine. Additionally, he serves on the Scientific Advisory Board of Sigma-Aldrich, on the American Chemical Society Committee for Professional Training and on the editorial board of the Journal of Biological Chemistry. Before joining GSK Copeland held scientific staff positions at Merck Research Laboratories, DuPont Merck and Bristol-Myers Squibb and a faculty position at the University of Chicago, Pritzker School of Medicine. Dr. Copeland received his B.S. in chemistry from Seton Hall University , his doctorate in chemistry from Princeton University and did postdoctoral studies as the Chaim Weizmann Fellow at the California Institute of Technology. His research interest is in elucidating the determinants of drug recognition by their biological targets, and the use of this information in the discovery and design of new medicines. He has contributed to drug discovery and development efforts across a wide range of therapeutic areas leading to numerous drug candidates entering human clinical trials. Dr. Copeland has contributed over 150 publications to the scientific literature, holds 8 issued U. S. patents and has authored 4 books in the areas of protein science and enzymology. His latest book, Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists (Wiley, Hoboken, NJ), published in March 2005.

Customer Reviews

Most Helpful Customer Reviews

7 of 7 people found the following review helpful:

5.0 out of 5 stars Drug developers need this book, March 10, 2006

By 

A. J. Cornish Bowden (Marseilles, France) - See all my reviews
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This review is from: Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists (Methods of Biochemical Analysis) (Hardcover)

Books and reviews on drug design are often disappointing, but Evaluation of Enzyme Inhibitors in Drug Discovery is excellent; it is a book that should be on the shelves of anyone involved in rational drug development, and available to anyone interested in understanding how successful drugs work. It starts by explaining why enzymes are appropriate targets for a drug design in the first place, and goes on to emphasize that inhibiting an enzyme and producing the intended effect on the whole organism is not a trivial matter. As the author remarks, "dogmatic arguments that lead to a priori predictions of what will work best in a biological context more often than not reflect an incomplete understanding".

If rational drug design is ever to become a reality it will involve knowledge of much more than three-dimensional structure, though this sometimes seems to be the only aspect considered. It requires, of course, knowledge of the different kinds of inhibition and how the inhibitor affects enzyme activity at different concentrations of substrates and products. In addition, it requires some knowledge of the metabolic context in which the inhibited enzyme is embedded: if it has almost no flux control then inhibiting it -- even to a high degree -- may have almost no effect on the flux through it (though it may still have large effects on the metabolite concentrations around it). finally it requires understanding of what makes some molecules "drug-like", and others not: it is no use identifying a superb inhibitor of the ideal enzyme if there is no way of delivering it to the target. Copeland deals with all of these points, and others, in an appropriately elementary way. Apart from giving much more information about inhibition than he did in Enzymes (Wiley-Interscience, 2000), here he takes a more leisurely pace and the book should not offer any serious difficulty to anyone wanting to master the subject.

As the author explains, there is much more to enzyme inhibition than just competitive inhibition: some successful drugs are indeed competitive inhibitors, Methotrexate and Viagra among them, but others are not; Finasteride, for example, used for treating benign hypertrophy of the prostate, is an uncompetitive inhibitor of steroid 5alpha-reductase. Classifying inhibitors thus needs more than crude measures of IC50 values, and if these are used at all they need to be used in conjunction with knowledge of how they relate to inhibition constants.

Analysis of the kind set out in the book is essential for understanding why enzyme inhibitors work as drugs, but the sceptical reader may wonder how much of it is post hoc rationalization, and how much was actually used for discovering the drugs. Let us consider the 26 enzyme inhibitors that have become successful drugs that are listed in Chapter 1, from Acetazolamide, an inhibitor of carbonic anhydrase used to treat glaucoma, to Viagra, an inhibitor of phosphodiesterase that is now familiar to everyone. Modern Drug Discovery claimed in 1998 that "Viagra was discovered using a rational drug design approach", but was it? It was not originally conceived as a drug for treating erectile dysfunction, and its usefulness for this discovered almost by chance when it was noticed that some men who participated in clinical trials as a treatment for angina pectoris reported unexpected effects. Even as an inhibitor for phosphodiesterase, Viagra was found by making variations on the structure of Zaprinast, a weak inhibitor that had failed to become a useful anti-allergy treatment. There is little in this history to suggest rational drug design.

There are many good points about this book, but it is often difficult to find them, because the index is very poor. For example, there is a discussion of the characteristics of "drug-like" molecules (Lipinski's rules, etc.), but don't expect to learn this from the index; the only way to find it is to leaf through the pages. Fortunately it comes early in the book, but there are other equally important and equally secret topics later on. In other respects this is a fine achievement, a book that can be enthusiastically recommended.

1 of 1 people found the following review helpful:

5.0 out of 5 stars Enzyme Kinetics, March 1, 2007

By 

Adrian M. Davies "A M Davies" (California, USA) - See all my reviews
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This review is from: Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists (Methods of Biochemical Analysis) (Hardcover)

I have found this book very useful. If you have to use enzyme kinetics, and analyze the data, then you really should have this book. That it is recommended by Prof Cornish-Bowden attests to its accuracy.
Personally I find this topic difficult, but this book is well written, and I have a much better understanding of kinetics after getting this book.

5.0 out of 5 stars Excellent explanations of enzyme inhibition, April 24, 2009

By 

Harvey Motulsky (Seattle, WA USA) - See all my reviews
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This review is from: Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists (Methods of Biochemical Analysis) (Hardcover)

Half of the drugs in use today work by inhibiting enzymes. This book explains the multiple ways that drugs can inhibit enzymes, and how to design experiments to determine the mode of inhibition. The book has lots of equations, but it isn't a mathematical book. All the concepts are clearly explained apart from the math. The writing flows nicely, so you can read it all to get an overview of the field. But it is clearly organized, with great headings, so it is also easy to use as a reference book.