Book Reviews
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 11 3935
Book Reviews Chemical Genomics. Edited by Ferenc Darvas, Andras Guttman, and Gycrgy Dorman. Marcel Dekker, New York. 2004. ix + 357 pp. 15.5 × 24 cm. ISBN 0-8247-5490-5. $134.00. This book lays a broad foundation for investigators interested in the new field of chemical genomics. The first chapter defines chemical genomics as the study of a wide array of cellular targets (usually proteins) by probing interaction with a wide array of small molecules, with the goal of expediting preclinical drug development by revealing (1) the functions of cellular components, (2) disease targets, and (3) new biologically active agents. Despite its name, chemical genomics as defined in this book does not necessarily involve genomic approaches. The book is edited by three experts in analytical chemistry and drug design who have assembled nine chapters authored by experts in diverse fields, although some chapters have only a tenuous connection to chemical genomics. Chapter 2 presents concepts of 3D protein modeling, structural databases, and software for modeling and validation. It briefly introduces the reader to the innovative concept of reverse docking, that is, the screening of a large database of protein structures for potential interaction with a small molecule, thus returning to the theme of chemical genomics. This is good reading for those who want an overview of structural modeling. Chapter 3 provides a thoughtful and logical consideration of those high-throughput screening (HTS) principles needed for studying large numbers of compounds interacting with large numbers of targets. Chapter 4 reviews the microchip and how it can be used in HTS using arrayed DNA, proteins, and small molecules. Chapter 5 continues with numerous HTS detection strategies and summarizes the previous chapters, to put all of the pieces together. Chapters 3-5 represent the crux of the book, covering the topics most relevant to chemical genomics. They survey an extensive number of subtopics and innovative concepts, such as kinomics (the broad study of the greater than 500 known protein kinases), surrogate ligand strategies, drugability profiling, photolabile caged substrates, and toxicogenomics. These chapters present technologies that are waiting for chemical genomics to begin bearing fruit. Despite the 2-year lag between the writing of these chapters and the publication of the book, the directions and ideas are still valid. The remaining chapters review several rather specialized topics that potentially interface with chemical genomics. Chapter 6 provides a very nice and informative description of photoaffinity labeling, with clever strategies for different applications. Consideration of how to move photoaffinity labeling in the direction of HTS is also covered. Chapter 7 presents the lipidome, which is defined as the entire lipid composition of a cell. Lipidomics is presented as the global study of the cellular state of lipids, their functions, associated proteins, and pathways. This chapter is primarily focused on lipids involved in signal transduction and therapeutic strategies. Analytical challenges of lipidomics are presented, and the lipid microchip for screening lipidinteractive proteins is described. Chapter 8 reviews the
focused topic of pharmacogenetics of dopaminergic pathway genes. Variant genes with polymorphisms of the dopamine receptors and a transporter protein are discussed. Finally, Chapter 9 addresses the field of DNA and protein sequence analysis. A specialized sequencematching algorithm for identifying patentable genes is proposed as an alternative to other well-known programs such as BLAST or FASTA, which are typically used for studying biological phenomena. Each chapter or group of chapters in the book has its own merits and will likely have its own readership. It is not likely that many readers will be interested in digesting all of the chapters. Chapters 1 and 3-5 clearly provide the basic foundation for chemical genomics, and they are well worth reading to obtain a perspective on the technologies involved. The other chapters stand on their own, and they are easy to read for an informative view of their respective topics. Bradford E. Windle Department of Medicinal Chemistry School of Pharmacy, Virginia Commonwealth University Richmond, Virginia 23298 JM058194M 10.1021/jm058194m
Methods and Principles in Medicinal Chemistry. Volume 22. Chemogenomics in Drug Discovery: A Medicinal Chemistry Perspective. Edited by H. Kubinyi and G. Miller. Wiley-VCH Verlag GmbH & Co., KgaA, Weinheim, Germany. 2004. xxiv + 463 pp. 18 × 24.5 cm. ISBN 3-527-30987-X. $179.00. This volume focuses on the general concept of chemogenomics in drug discovery. The book is divided into three main sections beginning with four chapters dealing with the general concept of chemogenomics. The first section discusses topics such as target family-directed masterkeys, drug discovery from side effects, the value of chemogenomics in drug discovery, and three-dimensional aspects in chemogenomics. The second section contains six chapters focusing on target families and contains discussions of molecular informatics in chemogenomics, chemical kinomics, kinases, ion channel modulators, phosphodiesterase inhibitors, and proteochemometrics. The final section contains five chapters that deal with the role of chemical libraries in chemogenomics. This section contains a review of compound libraries for G-protein-coupled receptors, computational filters for use in library creation, design of focused compound libraries, natural-product-derived libraries and the role of combinatorial chemistry in chemogenomics. In general, each of the 15 chapters is well-written and complete with clear figures and up-to-date references (to 2003). The book contains a very detailed and accurate subject index that covers the entire volume. There is no author index; however, this is not a serious omission in my opinion. Despite the excellent and well-crafted chapters, my enthusiasm for this book is dampened by the fact that the editors do not, in my opinion, accomplish their goal “... to re-position the core discipline of Medicinal Chem-
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Book Reviews
istry right in the center of chemogenomics.” Part of the difficulty lies in the lack of a working definition of the term “chemogenomics”. The editors and authors provided several definitions of chemogenomics with the most unrealistic, but common, definition being “... the discovery and description of all possible drugs to all possible targets.” Given the size of chemical space, this goal is impossible to achieve. Another definition provided is that chemogenomics seeks to discover smallmolecule ligands that modify or control biological systems. How is this definition different from the definition of medicinal chemistry? I am not sure. The editors also fail to contrast chemogenomics with other much-hyped disciplines such as chemical biology and chemical genetics. The failure of the editors to provide a detailed philosophical discussion of chemogenomics and to contrast it to “traditional” medicinal chemistry and other disciplines is a weakness of this book. However, readers hoping to learn about specific aspects of chemogenomics as described in the individual chapters will be rewarded with superb writing, good discussions, and excellent examples from the current literature. Thus, I recommend this book to all researchers interested in disciplines at the interface between chemistry and biology.
drugs for therapeutic administration are themselves chiral and may bind differently with the individual isomers to affect their bioavailability. This topic is addressed in Chapter 2, “Use of Chiral Excipients in Formulations Containing Chiral Drugs”. Chapter 3, “Transport of Chiral Molecules across the Skin”, considers another factor involved in the bioavailability of externally applied chiral drugs, i.e., stereoselectivity in penetration across the chiral skin barrier. In Chapter 4, “Stereoselective Drug Delivery through Prodrug Approach”, the prodrug approach to the design of agents capable of delivering isomers to specific sites is considered. A general overview of stereoselectivity in drug action, including some general principles relative to the biological discrimination of stereoisomers, description of stereochemical terminology, pharmacodynamic complexities, and examples of chiral agents with a variety of therapeutic actions is presented in Chapter 5, “Stereoselectivity in Drug Action and Disposition: An Overview”. The extensive literature relating to stereoselectivity in the pharmacodynamics and pharmacokinetics of drugs of a large number of therapeutic classes is effectively summarized in Chapter 6, “Stereospecific Pharmacokinetics and Pharmacodynamics: Selected Classes of Drugs”. Chapter 7, “Stereospecific Pharmacokinetics and Pharmacodynamics: Cardiovascular Drugs”, focuses on chiral drugs that act by a variety of mechanisms to treat cardiovascular diseases. Chapter 8, “Chiral Inversion”, provides a comprehensive appraisal of chiral bioinversion, i.e., the enzymatic or nonenzymatic conversion of one stereoisomeric form into another. In some instances, particularly with certain racemic drugs administered in modified-release dosage forms, stereoselective assays in comparative bioavailability studies are important. These are considered in Chapter 9, “Bioequivalency Determination of Racemic Drug Formulations: Is Stereospecific Assay Essential?”. The final chapter, “Regulatory Considerations in Drug Development of Stereoisomers”, deals with regulatory issues of importance in the development of new therapeutic agents with chiral center(s). It is interesting to note that relatively few racemic drugs have been reintroduced as a single isomer. This may be the consequence of both an inability to demonstrate clinical superiority of the isomer versus racemate and the marketing exclusivity period in the U.S. for developing a single isomer from a previously approved racemate, which is 3 years. All chapters include a comprehensive list of pertinent, up-to-date references, and the book concludes with a complete and adequate index. General principles of stereochemistry and its conventions, definitions, and models are described in various parts of the book. For nonchemists and students it might have been useful if these descriptions had been combined in an introductory chapter. Nevertheless, Chirality in Drug Design and Devepment provides an excellent overview of the various factors of importance in the design and development of chiral drug products. It will be of interest to both students and researchers concerned with the development of new chiral therapeutic agents.
Steven M. Firestine Division of Pharmaceutical Sciences Mylan School of Pharmacy Duquesne University Pittsburgh, Pennsylvania 15282 JM0582118 10.1021/jm0582118
Chirality in Drug Design and Development. Edited by Indra K. Reddy and Reza Mehvar. Marcel Dekker, Inc., New York. 2004. xii + 444 pp. 15.5 × 24 cm. ISBN 0824750624. $174.00. More than one-half of the drugs that are currently marketed exist as stereoisomers. Until 15-20 years ago, most therapeutic agents bearing a single chiral center were marketed as racemates. Indeed, in 1993 these mixtures comprised nearly 25% of all drug products. More recently, the emergence of elegant and effective chiral syntheses and separation techniques, coupled with the belief that pure single enantiomers would provide safer and more effective alternatives to racemates, has resulted in a greater emphasis on the evaluation and development of single isomers as drug products. Because most drugs are thought to produce their effects by interaction with a chiral biological target, it was the intuitive belief of many scientists that a single enantiomer would be superior to a racemic mixture; however, in many instances this notion has not been supported by clinical data. This book examines the complexities that explain these results. In 10 informative chapters, it addresses and reviews a multiplicity of events involved in the therapeutic response to chiral therapies. Chapter 1, “Effects of Crystal Structure and Physical Properties on the Release of Chiral Drugs”, considers the differences in physicochemical properties between a racemate and its enantiomers that may influence drug delivery because of differing solubility, dissolution, and stability. In addition, many of the pharmaceutical excipients used to formulate chiral
Carl Kaiser 8470 Woodland Road Millersville, Maryland 21108 JM058219H 10.1021/jm058219h
