Drug discovery: rational serendipity

B00KREVIEWS tRNA research: still going strong after four decades! tRNA Structure, Biosynthesis, and Function edited by Dieter $~Ii and Uttam L. RajBhandary, ASM Press, 1995. US$85.00 (member), US$99.00 (non-member) (xifi + 5 7 2 pages) ISBN 1 55581 073 X Transfer RNA (tRNA) is the adaptor molecule that transJates the information stored in nucleic acids into protein sequences. In the past decade, a great deal of progress has been made in our understanding of the structure and function of this central player in protein translation. The new textbook-sized volume entitled tRNA Structure, Biosynthesis, and Function describes many of these advances. This book is written and edited, without exception, by truly outstanding leaders in tRNA research. The opening chapter by the editors (Dieter S611and Uttam L. RajBhandary) sets the tone by summarizing the highlights in tRNA research over the last 40 years. The editors give the reader a sense of the impact tRNA research has had on our current understanding of RNA structure and function, as well as RNA-protein interactions. Although each of the 26 chapters that follows is self-contained and can be read in any order desired, I enjoyed the logical progression of the presentation, starting with Khorana's description of the first total synthesis of a tRNA gene. Beginning with this historical perspective and ending with two chapters describing interesting reactions that

Drug discovery: rational serendipity The Search for Anti-Inflammatory Drugs edited by Vincent J. Merluzzi and Julian Adams, Birkh&user, 2995. US$93.00 (314 pages) fSBN 3 7643 3683 4 The Search for Anti-Inflammatory Drugs is a collection of tales about the discovery and development of anti-inflammatory and immunosuppressive drugs. The first chapter presents a historical view of drug discovery. Therapeutics became a science in the early 18OOswhen, for the

322

TIBS 21 -

AUGUST 1996

involve modifications of amino acids attached to tRNAs, this book covers most, if not all, aspects of modern tRNAresearch. Chapters vary widely in style, as well as in depth and scope. Some authors chose to present a comprehensive review of a particular subject, while others provide a more succinct summary of a single topic. Examples of several comprehensive chapters include Sprague's thorough discussion of the complex eukaryotic transcription machinery, the encyclopedic summary of the primary, secondary and tertiary structures of tRNAs by Dirheimer, Keith, Dumas and Westhof, and Bj6rk's equally thorough discussion of modified nucleosides. The latter chapter alone contains 420 references! This brings me to another nice feature of this book, namely, the extensive bibliographies presented. Most chapters contain lists that are quite comprehensive and all references are (thankfully) complete with titles. In addition to providing an update to topics presented in previous volumes on tRNA, such as the organization of tRNA genes, modified nucleosides, tlLNA processing and tRNA identity, there are a number of chapters devoted to more recent discoveries and new directions in tRNA research. Examples of the latter include a chapter on 'Small Oligonucleotide Substrates for Specific Aminoacylation' by Martinis and Schimmel, an excellent review of the surprising discovery of a selenocysteineinserting tRNA by Baron and B6ck, and two chapters devoted to the first two high resolution co-crystal structures of tRNA-aminoacyl-tRNA synthetase complexes. The fast pace of tRNA research is perhaps best illustrated by the fact that at the time the chapters in this book were written, the crystal structures of only five aminoacyl-tRNA synthetases (including the two synthetase-tRNA complexes

described in detail) had been elucidated. Today, that number stands at 11! Alternate and unusual functions of tRNAs and tRNA-like structures are wellrepresented with chapters by Florentz and Gieg6 ('tRNA-LikeStructures in Plant Viral RNAs') and Putzer, GrunbergManago and Springer ('Bacterial Aminoacy]-tRNA Synthetases: Genes and Regulation of Expression'). Yarns and Smith propose a new 'Waggle Theory' in their chapter on 'tRNA on the Ribosome'. The chapter by Murgola entitled 'Translational Suppression: When Two Wrongs DO Make a Right' is sprinkled with musical headings ('What's it all about, Alfie?') and humorous mnemonics, and was one of the most enjoyable chapters to read. One interesting and relevant topic that deserved more discussion and perhaps even a chapter of its own, is the unusual function of host tRNAs as primers for retroviral reverse transcriptases. After reading this book, I would have to agree with Murgola, who concludes his chapter by stating that tRNA is no longer the 'Rodney Dangerfield of Molecular Biology' and that this key molecule in translation is finally getting the respect it deserves! 1would recommend this book not only to researchers in the tRNA field, but to all graduate students and researchers interested in nucleic acid biochemistry and RNA structure and function, in particular. The chapters are written by top-notch scientists, who have helped to advance our knowledge of the tRNA world and who will undoubtedly continue to move the field in exciting new directions in the years to come.

first time, pain-relieving substances were purified and administered in standardized doses. However, it was the synthesis of the drug salicylic acid (later modified to aeety]salicylic acid to improve efficacy and taste) by the entrepreneurial German chemist Herman Kolbe shortly thereafter that launched the pharmaceutical industry. This industry has since gone through a number of transitions in its quest for new drugs. Early approaches to drug discovery were purely empirical, or phenomenoiogical, requiring no understanding of an underlying mechanism. Drugs identified by chance or by modification of existing compounds were simply tested for relief of a target symptom. Such a symptom-based approach gave way to a mechanism-based approach. A major breakthrough in this area was the discovery by John Vane in 1971 that aspirin (acetylsalicylic acid) a~d other non-steroidal anti-inflammatory

drugs (NSAIDs)act by inhibiting prostaglandin biosynthesis 1. Vane's finding led to the discovery of new NSAIDs (described in the book) and, importantly, this marked a new phase of drug discovery in which a specific mechanism or enzyme is targeted. Drugs are now being sought against a wide range of cellular targets including adhesion molecules, proteases and signal transduction pathways. The third and newest phase is structure-based drug design whereby drugs are synthesized to fit and bind a target molecule of known structure. Whether this indeed turns out to be a viable strategy remains to be determined; none of the drugs described in The Search for Anti-lnflammatory Drugs were derived from a structure-based approach. The remaining chapters are individual case histories of drug discoveries at various pharmaceutical companies, written in narrative form by the

KARIN MUSIER-FORSY'rH University of Minnesota, Departmentof Chemistry, 207 PleasantStreet SE, Minneapolis,MN 55455, USA.

B00KREVIEWS

TIBS 2 1 - AUGUST 1 9 9 6

discoverers themselves. The drugs (often referred to only by isolate number) include cyclosporine, FK506, sulindac, zileuton, ICI204,219, ZD2138, MK0591, BIRM270 and azaspiranes. The authors emphasize different aspects of drug discovery and development (e.g. the screening process, chemical syntheses, clinical trials or doing science in a corporate environment), but otherwise describe remarkably similar experiences. First, one screens thousands of molecules to identify a lead compound. The lead compound is then chemically modified to generate many new derivatives each of which is subjected to a structure-activity relationship (SAR) study to correlate chemical structure with pharmacological activity. SAR results are the crucible of the industrial scientist; a bad SAR result and 'management' cancels the project - a good result and the project is allowed to survive, most likely only to be cancelled at a later date. A compound that passes the SAR test is then analysed for new parameters such as pharmacodynamics (how the drug is

metabolized in the body) and oral bioavailability (can it be taken as a pill). Compounds with good pharmacological activity are often further modified to increase bioavailability or solubility, for example, only to lose activity. The final trial is in the clinics where drugs are carefully screened for toxic side effects. A chemical structure with all the desired features is extremely rare and difficult, if not impossible, to predict. Finding the right compound is ultimately based on trial and error, regardless of how rational or well conceived an approach might be. A weakness of the book is a lack of objectivity. For example, the toxic side effects of drugs are often minimized. One frequently finds out about the severity of a drug's side effects only by reading a chapter written by a competitor. This is perhaps not surprising as the book is by members of industry writing about their own products. Reading this book, one gets the impression that discovering and developing a drug is akin to the board

game Monopoly, with its own set of pitfalls, but with the similar final objective of a strong market position, if not an outright monopoly; the wild card in the drug 'game' being the seemingly befuddled decision making process of management, which the scientists appear to have to navigate around to keep projects alive. However, making a drug and bringing it to market is far from a game, but rather a risky competitive business requiring large amounts of real money, hard work, perseverance and luck. Thus, having many of the elements of a good story line, the book is indeed entertaining for both insiders and those only peripherally associated with the drug industry.

Clear and simple

of these in detail, discussing their relative merits and uses. By means of many original illustrations, each accompanied by brief descriptions, she shows the results that can be achieved. A brief outline is included on the possibilities now available for digitizing and editing scans, ultrasound and video images, etc. in photo-manipulation programmes. The chapter on molecular graphics explores, in detail, genetic sequences, restriction maps and molecular models. She discusses the various software packages that are available for sequencing and modelling, and correctly advises looking for a programme that has good graphical capabilities, or at least one that allows data transfer to a drawing programme for further editing. The author suggests that you look critically at graphs in journals, slides and posters and try to analyse them, and ask yourself how you could improve them. You will have no trouble with that task if you digest her chapter on graphs and associated software; it is extensive and very useful. Not only does the author explore different types of illustration, she also discusses the various media in which they will be used: publications, lecture slides and poster presentations. The editor of TiBS would, I'm sure, appreciate authors taking note of the chapter dedicated to 'The Journal Figure', in particular journal instructions concerning figures and proofing requirements. A slide is usually viewed for less than 30 seconds and so its impact must be immediate. A good slide makes no more than three points and these points emphasize the speakers's words - less is more. The author shows how to build a

progression of information through a series of slides rather than trying to fit everything on one slide. She also suggests appropriate software for sourcing slides and overheads. You get the feeling that you need to master at least half a dozen different programmes here! When considering presentation by means of the poster, Ms Briscoe remarks that many in your audience have reached the 'bifocal age' and will have difficulties focusing on small type. Content, text layout, production and purpose are all covered in depth and the author urges you not to be afraid to be simple, clear and creative. Even in the age of the computer, there is a place for hand-drawn figures. The book includes tips and tricks for doing your own figures whether using a computer or drawing by hand. You can learn to present visual information clearly and concisely, with awareness, a clear purpose, time, patience and practice. But fear not, help is at hand in suggesting ways of communicating with a professional illustrator, if only for advice! I would suggest that this book would be a useful purchase for any scientist or scientific artist. Virtually every type of figure and situation is covered. Having read right through the book to achieve an overview, information is easily accessed by reference to the clear contents pages. My review copy is already well-thumbed!

Preparing Scientific Illustrations: a guide to better posters, presentations and publications (2nd edn) by Mary Helen Briscoe, Springer-Verlag, 1996. DM44.00 (xii + 204 pages, 206 illustrations) ISBN 0 387 94581 4 'The information is obvious. If they don't understand it, that's their problem.' In reality, the 'problem' is more likely to be the communicator's. Every scientist must be aware of the need to present research data in a visual format that will complement and enhance the written or spoken word. Ha! Easier said than done you may say. But Mary Helen Briscoe aims to help you make effective choices by pointing out some principles of good visual communication, and by showing examples of good and bad choices. The emphasis of this book is on the intention to communicate ideas and learning to clarify those ideas by visual means: by illustration. Right from the first pages you will be shown fundamental ways of clarifying information and improving the look of diagrams. You will find tips on what makes a good illustration as well as a really useful section on planning figures. Drawings, photographs, charts, tables and graphs can all be effective vehicles of communication. Ms Briscoe explores each

Reference

1 Vane, J. R. (1971) Nat. NewBiol. 231, 232-235

MICHAEL N. HALL Department of Biochemistry, Biozentrum, University of Basel, CH 4056 Basel, Switzerland.

SHEILA BETTS* Cambridge, UK. *Sheila Betts is the scientific artist responsible for transforming TiBSfigures.

323