This page contains the full text of a letter
from M. L. Cárdenas and A. Cornish-Bowden
to the Editor of Science entitled
Metabolic Analysis in Drug Discovery and
published in Science 288, 618–619 (2000), together with a response fom
Dr Jürgen Drews.
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
31 Chemin Joseph-Aiguier,
Boîte Postale 71,
13402 Marseille Cedex 20, France.
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.
International Biomedicine Management Partners,
and Orbimed Advisors,
New York, NY 10017-2023, USA.
E-mail: email@example.com or firstname.lastname@example.org
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.