J. Med. Chem. 2009, 52, 4977–4978 4977
Computational Drug Design. A Guide for Computational and Medicinal Chemists. Edited by David C. Young. John Wiley & Sons, Inc., Hoboken, NJ. 2009. xxxvi + 307 pp. 16 24 cm. ISBN 978-0-470-12685-1. $100.00. This book is a standalone volume intended to illuminate the ways that computational techniques are utilized in the drug design process. It is quite industry oriented and was never intended to deal with the fine details of each of the many described techniques but to present computational drug design for a wide audience. After a brief introduction focused on the economic motivations for computerbased techniques in drug discovery, the remainder of the book is divided into three parts. Part I describes “The Drug Design Process” by explaining some of the underlying considerations for obtaining a “drug”, e.g., ADMET and target discovery and validation. Next, chapters differentiating between design paradigms for known and unknown protein enzyme targets and other, e.g., DNA, RNA, and receptor, targets are followed by a chapter describing computational considerations and processes for chemical library design. Part II is the heart of the text with chapters describing “Computational Tools and Techniques”. Many chapters are very short, and a few are probably inadequate to convey any understanding, but each is supplemented by leading references in loosely categorized bibliographies. The topic list here comprises essentially the full spectrum of computational techniques; including homology model building, molecular mechanics, docking, pharmacophore models, QSAR, cheminformatics, and automation of tasks. How these topics fit together in terms of actually designing a drug is evident. The final group of chapters, “Related Topics”, includes descriptions of other technologies that are at least partially in the drug discovery canon, e.g., bioinformatics, synthesis route prediction, and proteomics. The last chapter is a gaze into the crystal ball of scientific developments impacting health care and the ability of pharma to rationally and profitably respond. Overall, the book has been written in very lucid and readable language. The text is organized nicely and is perhaps a must have for someone desiring a quick overview of computeraided drug design, e.g., pharmaceutical scientists wishing to understand what computational tools are available to them, without becoming experts in the field. However, for readers with little knowledge, many excursions into the references will be necessary to grasp even some of the basic principles. For example, the chapter on molecular mechanics does not really explain this key enabling technology behind nearly all of the other techniques. In contrast, other than several interesting quantitative software performance comparisons, practitioners would probably find little in this text to be new or unfamiliar. Finally, while the concept of using screen shots from commercially available software packages to provide the bulk of the book’s figures is clever because it gives the user’s viewpoint on the software, the execution is compromised by only providing black and white figures in the text, even though color plates were supposed to be available on the accompanying CDROM. Additional references and a selection of free software and product literature provided by a few commercial software vendors are also missing from the CDROM, which
in the reviewers’ copy has been incorrectly mastered. In summary, this text is very accessible but its limited depth of detail will probably appeal to a somewhat narrow audience. Aurijit Sarkar and Glen E. Kellogg* Department of Medicinal Chemistry Virginia Commonwealth University School of Pharmacy Richmond, Virginia 232980540
DOI: 10.1021/jm900605k Published on Web 06/01/2009
Handbook of Drug Metabolism. Second Edition. Edited by Paul Pearson and Larry Wienkers. Informa Healthcare, New York. 2009. xii þ 694 pp. 18.5 26 cm. ISBN 978-14200-7647-9. $329.95. This book is divided into four sections: Fundamentals, Factors Affecting Drug Metabolism, Technologies, and Applications. Overall, this is a reasonable update of the last edition that is a good primer for chemists entering the field of medicinal chemistry. The brevity of many of the chapters means that this title will not be the only book required, but it does provide good fundamentals. Missing from the book are dedicating chapters on the use of computational methods, detailed chemical mechanisms, and the proteomics of drug metabolizing enzymes. The section on fundamentals includes Chapters 1-6 and provides an overview of the areas of interest in drug metabolism. Chapter 1 is an overview of the history and multidisciplinary nature of drug metabolism. The author does a very nice job of illustrating the chemical history and the multidisciplinary nature of the study of drug metabolism. Chapter 2 details the difficulties associated with the pharmacokinetics of metabolites. Initially a series of simplifying assumptions is made, and equations are presented. Specific examples help in understanding the limits of the equations for different rate-limiting steps. Later, more complicated situations are considered. Overall, it is a good introduction to metabolite pharmacokinetics. Chapter 3 details the fundamentals of liver anatomy and physiology. The different cell types are described, as are subcellular organelles. This chapter would be of interest to chemists looking to understand the fundamentals of cell biology of the liver. Chapter 4 is on the fundamentals of cytochrome P450. This chapter gives a concise explanation of P450 nomenclature, which is useful for those who are new to P450 enzymology. The general catalytic cycle is described, as are reactions catalyzed by the enzyme family. Brief descriptions of mechanism are also given for some of the reactions. In Chapter 5, three different enzyme systems that can mediate substrate oxidation are discussed: flavin monooxygenase, xanthine oxidase, and aldehyde oxidase. The section on aldehyde oxidase is particularly timely, since at present over 40 drugs are metabolized by this enzyme, and the increased use of nitrogen-containing heterocycles means that a greater fraction of new drugs will be metabolized by these enzymes. Thus, this section provides a valuable resource for the medicinal chemist. The final chapter in this
4978 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15
section is on UDP-glucuronosyltransferases and provides concise information about this enzyme system with a very useful table as an appendix of endogenous substrates, drug substrates, inducers, and inhibitors. The next section of the book includes Chapters 7-13 and covers factors that affect drug metabolism: genetics, age, and drug-drug interactions, as well as organ specific sites of metabolism. The short chapter on pharmacogenetics outlines mainly P450 enzymes, UDP-glucuronosyltransferases, and the historically important N-acetyl transferases. While this area has been very heavily studied, the translation of this research to clinical settings as always remains in the future. A well referenced chapter on the inhibition of drug metabolizing enzymes outlines the most common basic modes of inhibition, followed by examples for different drug metabolizing enzymes. The important area of inhibition by sequential metabolism is not addressed. The remaining chapters in this section are very biological and may provide a good resource for chemists interested in the biology of these systems. The third section addressing technologies used in drug metabolism is the most chemical, and it relates well to early drug development. In keeping the first chapter of this book, drug metabolism remains a very multidisciplinaryendeavor, and diverse topics from small molecule analytical chemistry, LC/MS, and NMR are presented in Chapters 14 and 15. Other sections outline methods often used in drug discovery such as in vitro metabolism, drug-drug interactions, and enzyme induction. A well thought-out chapter on mechanism based inhibition of P450 enzymes covers the criteria used for establishing mechanism-based inhibition and methods for characterizing the enzyme. A partial list of functional groups
Book Reviews
that undergo mechanism-based activation is given; however, a more exhaustive list would have enhanced this chapter significantly. The characterization sections and the helpful kinetic analysis make this chapter a very good resource for chemists interested in this area. The final section on application of metabolic studies to drug discovery and development provides an overview of the regulatory process, a well-done chapter on determining the potential for covalent binding, the use of transgenic animals, and modeling pharmacokinetics. Most of these chapters are aimed toward people active in the field, with Chapter 23, on covalent binding, being of the most interest to the chemist. This book has a number of chapters that address continuing concerns in drug metabolism. One of these is Chapter 9, which discusses the complicated and difficult-to-address issue of developmental differences in metabolism. Other chapters include the uses of NMR in drug metabolism, as well the problems and advantages associated with the use of recombinant enzymes. However, while this book would prove useful for a chemist new to the field, it is mainly oriented toward scientists active in drug metabolism research.
Jeffrey P. Jones Fulmer 455 Department of Chemistry Washington State University Pullman, Washington 98164-4630
DOI: 10.1021/jm900645s Published on Web 06/22/2009
