Metabolic Analysis in Drug Discovery

Letter from M. L. Cárdenas and A. Cornish-Bowden
Response from Jürgen Drews
Comments on the response (not published in Science).

Letter from M. L. Cárdenas and A. Cornish-Bowden

Metabolic Analysis in Drug Discovery
Science 288, 618--619 (2000)

The special issue on drug discovery (17 Mar., pp. 1951-1981) focuses on the revolution being brought about by the Human Genome Project, making almost no direct mention of metabolism. Numerous illnesses are disturbances of metabolism, and many drugs act by altering metabolism. The implied assumption is that once an enzyme inhibitor has been identified and a means found for delivering it to its target, the metabolic consequences are so obvious that they do not need to be thought about in advance. However, partial inhibition of a typical enzyme has little or no effect in vivo (1). Coping economically with huge increases in the number of potential drug targets that genomic science is uncovering--from about 500 molecular targets in current drug therapy to as many as 100,000 human gene products--will require procedures for eliminating the useless ones in advance. Such a screening process will require metabolic simulation (2) supported by mathematical methods for converting lists of gene products into metabolic pathways (1). Of the current molecular targets, about 30% are enzymes and 45% are receptors, and few if any are genes, so referring to 100,000 human genes as potential drug targets, as Bruce Agnew does in his News article (When Pharma merges, R&D is the dowry, 17 Mar., p. 1952), is to focus attention in the wrong place.

With little attention being paid to metabolism with regard to drug discovery, it is not surprising that, as J. Drews points out in his Review (Drug discovery: A historical perspective, 17 Mar., p. 1960), few leads and development compounds, if any, can be credited to the new drug discovery paradigm, which relies on the economy of numbers afforded by the advances in genomic science and related technologies. Nor is it surprising that genetic validation of targets can be misleading, as J. Rosamond and A. Allsop mention in their Review (Harnessing the power of the genome in the search for new antibiotics, 17 Mar., p. 1973). An uncritical assault on the thousands of new targets revealed by the Human Genome Project might prove to be just trial and error in new clothes.

María Luz Cárdenas
Athel Cornish-Bowden
CNRS-BIP,
31 Chemin Joseph-Aiguier,
Boîte Postale 71,
13402 Marseille Cedex 20, France.

E-mail: cardenas@ibsm.cnrs-mrs.fr

References

A. Cornish-Bowden and M. L. Cárdenas, Eds., Biotechnological and Medical Implications of Metabolic Control Analysis (Kluwer, Dordrecht, Netherlands, 2000).
R. Eisenthal and A. Cornish-Bowden, J. Biol. Chem. 273, 5500 (1998).

Response from Jürgen Drews

Metabolic analysis is by no means forgotten, as implied by Cárdenas and Cornish-Bowden. What is often called target validation must eventually include this type of analysis. As I discussed in my Review, the functional role of a particular target must be understood. Structural genomics, the systematic study of the three-dimensional structure of all proteins, will be helpful in this regard (1, 2), as will traditional biochemistry and pathophysiology. Contrary to Agnew's reference in his News article to 100,000 genes in the human genome as potential drug targets, my colleagues and I have estimated, using genetic and biochemical data, the number of potential drug targets to be in the range of 5000 to 10,000 proteins, a figure that has since been broadly cited in the literature related to drug discovery (3).

Many drugs, such as antibiotics, have been around for several decades, and many were found empirically. This, however, does not invalidate approaches that target the molecular mechanism of action of new drugs. Without exception, antibiotics elicit their effects by modifying a single molecular target in a highly specific way. Finally, there are many ways to select potential drug targets from the around 100,000 human gene products. Genetic and biochemical tools as well as the methods of developmental biology are at our disposal. There does not have to be an uncritical assault on thousands of new drug targets, as Cárdenas and Cornish-Bowden imply.

Jürgen Drews
International Biomedicine Management Partners,
Basel, Switzerland,
and Orbimed Advisors,
New York, NY 10017-2023, USA.

E-mail: drews@nigeons.com or drews@biomedicine.ch

References

S. K. Burley et al., Nature Genet. 23, 151 (1999).
P. F. Lindley, Acta Crystallogr. D 55, 1654 (1999).
J. Drews, in Human Disease-From Genetic Causes to Biochemical Effects, J. Drews and S. Ryser, Eds. (Blackwell, Berlin, 1997), p. 7.

Comments on the Response

Note. These comments did not appear in Science; they have been added afterwards.

It is of course a comfort to know that metabolic analysis is by no means forgotten, but it remains a pity that Dr Drews and the authors of the other articles in the supplement on drug discovery forgot to make any mention of it. We hope that they will take steps to ensure that readers of their writings on this subject realize the importance of metabolism in what they are doing, even if it is only something that target validation must eventually include, which is actually to put it very mildly. Taking account of metabolic analysis only eventually rather than at the outset seems a sure way to ensure that a lot more time and effort will be wasted.

Page created on 22 May 2000
Last update: 11 February 2002
Comments to Athel Cornish-Bowden

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