TiPS - April 1993 [Vol. 141

electrified black boxes, vitamins unknown to science, and the ability of amygdalin (‘laetrile’) to cure cancer stems from causes more complex than lack of intel- ligence. Among these are the American egalitarian tradition and the inveterate national opti- mism that no problem is intrinsi- cally without a solution. If ‘all men are created equal’, then any- one’s opinion is as good as that of his physician, and so Americans tend not to show that deference to physicians so characteristic of other Western countries. We also believe in freedom of choice. We believe there are constitutional rights of self-dosage and access to unproven remedies, and if our doctor can’t do anything about our cancer, chronic arthritis, over- weight bodies, or attenuating sexual prowess, then we are some- how going to find a treatment for ourselves. And so we add our dollars to the $500 million spent each year on unproven cancer remedies and the billions spent on

so-called health foods and herbs. After the Food and Drug

Administration and the National Cancer Institute announced that amygdalin, a cyanogenic glyco- side from apricot seeds, christ- ened vitamin Brr by true believers, was without efficacy in the treat- ment of cancer, it was banned by the Federal Government. The out- cry was such that more than half of the States have legalized the use of amygdalin by cancer patients. Am’ so it continues to be used, along with the other cancer ‘treatments’ of reflexology, iridology and ioniz- ation therapy.

Young does not exempt the medical profession itself from his strictures. Physicians in North America have often been guilty of outright quackery, from Dr Abrams and his electronic box, which diagnosed and cured dis- eases hundreds of miles away (after your cheque had cleared the bank), to the Drs Kaadt who treated diabetics with vinegar instead of insulin. When Dr

135

Abrams died in the 192Os, he was

a multimillionaire. A distinguishing feature of the

North American use of unproven or disproven remedies is the extent to which they are taken to prevent rather than cure con- ditions. This is perhaps an indi- cation of how much Americans worry, despite their optimism. We worry about cancer, exercise, eating, aging and our cholesterol levels in a manner worthy of study by sociologists and anthropol- ogists.

I recommend this volume as a rattling good read. However, it is likely to give you a sore neck from all the head-shaking it will en- gender. For the soreness, I suggest one aspirin, followed by two fingers of whiskey and a spoonful of honey in a glass of hot milk. Send payment to the address given below.

RYAN J. HUXTABLE

Deparfmerlf of Pharmacorogy, College of Mediche, University of Arizona, Tucson, AZ 85724, USA.

A structure too far The Design of Drugs to Macromolecular Targets

edited by C. R. Beddell, Wiley, 2992. E60.00 (xiv + 247 pages) ISBN 0 471 92080 0

This book tackles a particularly controversial topic, given the continued debate about exactly what constitutes drug design. One very narrow interpretation, which the current discussion has focused on, is the use of structural infor- mation, either known or inferred, about target macromolecules to tailor new chemical entities as potential drugs. Although at one stage it is pointed out that ‘over- simplistic presentation of its potential has led to unrealistic expectations’, most of the authors have still fallen into the trap of assuming that the success of modern structurallmodelling methodology is measured in terms of an immediate payoff in drug discovery rather than in terms of ideas generated.

Unfortunately, even in the most highly (crystallographically) resolved systems, events such as changes in protein conformation upon binding different ligand classes, or unexpected binding

modes, can destroy our imagined knowledge base.

Following an overview of the diverse range of macromolecular drug targets that promises us an exciting insight into what may be achievable now and in the near future, there is a feeling of being let down by both the age and the variety of the selected examples presented in subsequent chapters. Despite the overall objectives of the book, we are drawn to the conclusion that true drug design (measured as described above) has rarely, if ever, been achieved, since most of the discussion simply relates to after-the-event rationalization, rather than to the predictive value of the approach. For example, methotrexate ‘is a very potent inhibitor of almost all DHFRs [dihydrofolate reductasesl . . . developed. . . before DHFR was a known entity’. Similarly, despite 20 years of living with the detailed structure of haemoglobin, ‘there are as yet no drugs in the clinic arising from this [design] approach’. As a further illus- tration, we are asked to believe that ‘detailed information of g- lactam D-D-peptidase inter- actions. . . could be of use in designing new analogues of fi- lactams’. Given the thousands of

penicillins, cephalosporins, etc. already synthesized, and the multi-dimensional pharmaco- kinetic hurdles associated with their development into drugs, this may indeed be a challenge too far for modelling techniques!

On a positive note, the treat- ment given to these now classical structural problems is most accept- able if the reader requires an informative record of the research and the associated lessons to be learned. In this respect the book will be of interest to medicinal chemists rather than to expert modellers or structural chemists, who will have alre.rdy encoun- tered more detailed accounts else- where. It is not an introductory text, however. Particularly stimu- lating are the chapte:s describing thyroid hormones, DNA-drug complexes and glycolytic enzymes. If only the theme had been devel- oped using more up-to-date examples, and the utility of struc- tural information was placed more into context alongside other tools available to the medicinal chem- ist, the result may have been much more exciting.

JOHN SAUNDERS

Glaxo Crovp Research Ltd. Gremford Road. Greenford, Middlesex, UK U&i OHE.