TiPS -July
1990 [Vol. 211
structure to the differences in function between insulin IGF, EGF and PDGF receptors would have been most welcome. This could have emphasized the fact that whilst these receptors all express tyrosyl kinase activity and, in some instances, are co-expressed on cells they can exert different cellular effects. Espinal’s treatment of the metabolic effects of insulin is coupled with a good analysis of how it interacts with various signalling pathways, providing an excellent, cogent overview. This is a refreshing analysis, as all too often reviews of insulin action focus solely on its downstream effects on glucose and fat metabolism - a reflection of the experimental approaches taken to find means of preventing insulin resistance and which are targeted at attacking a
Drug design of the third kind Computer-Aided Drug Design: Methods and Applications edited by T. J. Perun and C. L. Propst, Marcel Dekker, 1989. $99.75 in USA and Canada ($119.50 elsewhere) (vi + 516 pages) ISBN 0 8247 8037 X There are three ways to discover new drugs. The first is blind
297 symptom, namely hyperglycaemia, rather than the underlying cause, namely a failure in receptor signalling. This brings us to diabetes - a major and growing health problem in Western societies. Whilst diabetes is alluded to in the first two chapters, it is in Chapter 3 that Espinal begins to define the two groupings: type I or insulindependent diabetes; and type II or non-insulin-dependent diabetes. Contrary to popular perception, it is the latter group that predominates. Unfortunately the discussion of type II diabetes is not very elucidative, which is a pity as it needs to be clearly stated that this is not one disease but a condition which can arise for a variety of complex reasons. Indeed, the first two chapters leave one with the impression that type II diabetes is
a problem solely of poor responsiveness of islet cells to secrete insulin in response to elevated glucose levels. Finally, I noticed that the author could not resist listing clinical symptoms, and whilst we are told what polydipsia (thirst) is, I wonder how many non-medical undergraduates are au fait with ‘nocturnal enuresis’ and ‘amenorrhoea’, for example. Espinal’s book touches on all the key areas of insulin’s production, structure and action. Anyone would profit by reading this book and there is no doubt that it would provide a useful addition for undergraduate reading if it were cheaper and formed part of a course accompanied by tutorials.
screening of libraries of compounds, regardless of structures. The screen can be as simple as binding or as complex as behavior. Blind screening has largely been replaced today by mechanistic methods, in which structure-activity relationships are determined through chemistry-biology dialogue. Active compounds are changed only conservatively, then tested, and the results affect the next compound designed. Each
new molecule is a measured learning step, rather than a stab at discovery. A working model of the receptor itself emerges from this iterative process. This, more rational, second approach is more successful than blind screening. Medicinal chemists dream of a third way to create drugs. The biological target - receptor, enzyme, or ion channel - must be purified and crystallized, then submitted to X-ray diffraction analysis. These data permit a
MILES
D. HOUSLAY
Molecular Pharmacology Group, Department of Biochemistry, University of Glasgow, Glasgow G12 SQQ, UK.
TiPS - July 1990 [Vol. 111
298 three-dimensional map of the receptor molecule to be built, and, if the crystals are doped with l&and, should betray the active site as well. Armed with a true map of the receptor, the chemist may see the target, and the molecule interacting with that target. The chemist draws a hundred molecules in an afternoon on a computer terminal and tests them on the comThis receptor. puter-modeled identifies the structure of just one highly active and original compound, which is then synthesized. A year’s work is accomplished in a day, without getting anybody‘s hands wet. It is this silicon-intensive approach of the third kind that is the focus of Computer-Aided Drug Design (CADD). The Dreiding and CPK plastic models of molecules have yielded to the Evans and Sutherland three-dimensional images on computer terminals, which allow superimposition of molecules and ‘docking’ of ligand to receptor. With any of a dozen commercially available software packages, optimal conformations can be predicted and various maps of compounds - electron density, solvent-accessible surface, etc. - can be generated. Two-dimensional nuclear magnetic resonance data can be analysed for nuclear Overhauser effect (NOEL which can show when protons come in close inter- or intramolecular proximity (2.5-3 A). NOE is particularly useful for determining three-dimensional configurations of large, loose ligands such as peptides in solution. These configurations can be very different from those determined by X-ray crystallography, or in the ‘gas’ state determined by molecular modeling - but also very different from the configuration when bound to the receptor! The CADD method is still more dream than reality. NMR is generally limited to measuring high concentrations of small molecules in solution, thus excluding 99% of the interesting cases, which concern the bound complex of high affinity ligands present in low concentrations with large receptors (>lO kDa). Relatively few receptors of medical interest have been, and perhaps just a minority can be, crystallized. Finally, the software packages for predicting conformations of small molecules too often fail to predict correct
conformations, without NMR or crystallographic input. That it will be possible to develop drugs through CADD is clear, none the less. T. J. Smith describes how X-ray crystallography elucidated the threedimensional structures of picomaviruses, and determined the site of action of the Winthrop antiviral drugs. These viruses bind to receptors on the cell via a highly conserved protein in a canyon floor. The antiviral drug WIN52804 binds in a pore under the canyon floor, and may act by altering the conformation of the canyon. This chapter is written in a clear and simple style, which is within the grasp of the non-specialist. CADD requires the interaction of computer experts with chemists and biologists of various perComputer-Aided Drug suasions. Design ought to make the subject approachable by specialists from different areas. The first six chapters deal with methodology primarily molecular modeling and NMR - but only the X-ray crystallography chapter by D. J. Abraham makes the subject approachable for the novice. The last six chapters recount applications of CADD; of these, T. J. Smith’s chapter on
viruses and D. G. Hangauer’s on angiotensin-converting enzyme inhibitors are excellent. The chapters on renin inhibitors, opioid peptides, dihydrofolate reductase and a somatostatin-like receptor all make valuable contributions, but do not completely lay down the foundations. Computer-Aided Drug Design also fails to satisfy some needs of CADD specialists. For instance, there is a list of the dozen molecular modeling software packages available, but not of their relative merits. The very important need to perform searches on threedimensional, electrostatically defined libraries using systems such as MACCS (molecular access system) is not addressed. The contributors to this book successfully avoided the potential catastrophe of presenting a smorgasbord of all possible computer applications in drug discovery. Instead, they helped to define CADD - the method that allows us to open our eyes and see the target, instead of shooting in the dark.
What can it be?
afoot to form a society. Given this momentum, who would cavil at a mere definition? When I use a word, it means precisely what I want it to mean, murmurs the incipient pharmacoepidemiologist. Indeed, despite its proselytory note, this book fills a gap. It reviews how information is obtained on the desirable and undesirable actions of .a drug after it is introduced into clinical use, and has many useful insighis on the regulatory process in the USA. The .his?orical development of the Food and Drug Administration is described, and if you have ever been confused by acronyms such as JCPDU, ETIP, ADR, or OEB, this is the place to unconfuse yourself. Specific monitoring systems for adverse drug reactions are described in detail, separate chapters being devoted to the Group Health Cooperative of Puget Sound, the Kaiser Permanente Medical Care Program and others. The various case histories supplied are readable and informative. In recent years, four drugs
Pharmacoepidemiology edited by Brian L. Strom, Churchill Livingstone, 1989. E55.00 (xvi + 424 pages) 1SBN 0 443 08675 3 This book is an unwitting text on how to invent a discipline, with special notes on the devising of an arcane jargon. It is an exercise in scholarly territoriality, the academic equivalent of urinating on the boundaries of one’s domain. What is pharmacoepidemiology? The definition given is that of the use and effects of drugs in large numbers of people. Drop out the word ‘large’ and you have a reasonably concise definition of pharmacology. Indeed, the difference introduced by that monosyllabic adjective is not at all clear. But never mind. Pharmacoepidemiology has an annual ‘international conference’, which although held in Minneapolis can be taken as a priori evidence that the field has arrived. There are two new journals devoted to the topic, and plans are
JOHN
LEHMANN
Concorde Bio, 21 rue de I’Etoile, 92500 RueilMalmaison, France.