Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists
Product Description
Vital in rank for learning and optimizing new drugs
“Understanding the data and the experimental details that support it has everlastingly been at the heart of excellent science and the assumption challenging administer that leads from excellent science to drug discovery. This book helps medicinal chemists and pharmacologists to do just so that in the realm of enzyme inhibitors.”
-Paul S. Anderson, PhD
This publication provides readers with a thorough understanding of enzyme-inhibitor evaluation to help them in their efforts to learn 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 matter-of-fact 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 means?
* 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 in rank 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 unique forms of inhibition that are commonly encountered in drug discovery efforts, but can be easily overlooked or misinterpreted.
This publication is calculated 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.
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Half of the drugs in use today work by inhibiting enzymes. This book clarifies 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 clarified 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 fantastic headings, so it is also simple to use as a reference book.
Rating: 5 / 5
I have found this book very helpful. If you have to use enzyme kinetics, and question the data, then you really should have this book. That it is not compulsory by Prof Cornish-Bowden attests to its accuracy.
Personally I find this topic trying, but this book is well written, and I have a much better understanding of kinetics after getting this book.
Rating: 5 / 5
Books and reviews on drug design are often disappointing, but Evaluation of Enzyme Inhibitors in Drug Discovery is brilliant; it is a book that should be on the shelves of anyone caught up in rational drug development, and available to anyone interested in understanding how successful drugs work. It starts by explaining why enzymes are apt targets for a drug design in the first place, and goes on to emphasize that inhibiting an enzyme and producing the proposed effect on the whole organism is not a trivial matter. As the author explanation, “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 nearly no flux control then inhibiting it — even to a high degree — may have nearly no effect on the flux through it (though it may still have large effects on the metabolite concentrations nearly 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 in rank 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 theme.
As the author clarifies, 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 really used for learning 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 handle glaucoma, to Viagra, an inhibitor of phosphodiesterase that is now familiar to everyone. Modern Drug Discovery claimed in 1998 that “Viagra was exposed 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 exposed nearly by opportunity 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 helpful anti-allergy treatment. There is small in this history to suggest rational drug design.
There are many excellent points about this book, but it is often trying 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 guess to learn this from the index; the only way to find it is to leaf through the pages. Opportunely it comes early in the book, but there are other equally vital and equally secret topics later on. In other respects this is a fine achievement, a book that can be enthusiastically not compulsory.
Rating: 5 / 5