On 17 Jan 1997, Athel started a discussion on the following note:
> Issue 6604 of Nature (7 November 1996) has a supplement entitled
> "Intelligent drug design". ...[It] appears not contain the words
> "metabolism" or "metabolic", and appears to display no recognition of
> the fact that what cells do is metabolism and that what drugs are
> supposed to do is to alter metabolism. .................. I suppose
> the basic assumption is that once you find the sought-after competitive
> inhibitor of the key enzyme and find a way of delivering it to the
> target cell its effects in vivo are so obvious that they don't need to
> be thought about in advance.
Obviously, many of the participants in this group have thought about this
question, and a few have even been brave (or foolhardy) enough to try and do
relevant experiments. I think it might be helpful to inform the group of
two things: 1) An indication that there is some institutional interest in
the problem, and 2) A brief story about one "Drug Target" problem that
several people have explored, with an invitation to modellers to help
think about it.
On June 18-19, 1996, there was a small "Workshop: Gene Networks and
Cellular Controls" held at the Hotel duPont in Wilmington, Delaware,
sponsored by the [United States] Office of Naval Research (which FUNDS
extramural research), organized and run by FASEB [Federation of American
Societies for Experimental Biology] and also supported (I think) partly by
duPont. It was an unusual mix of topics and people, but Hans Westerhoff
was among the invited speakers (and made important contributions to all
the discussions), and there were at least a few talks on metabolic pathway
dynamics (B. Ogunnaike, R. LaRossa, D. Fraenkel, D. Chipman, G.
Stephanopoulos, T. ap Rees). At the close, the representative of the
Biological Science and Technology Division of ONR (Dr. Eric Eisenstadt, I
believe) said that ONR would like to consider funding of more research in
control theory and experiment along the lines discussed .... I don't know
whether anything concrete has come of this yet.
My "story" is not really about a drug (yet), but about herbicides.
Herbicides are conceptually like drugs, in that one wants them to depress
or destroy one kind of cell or organism without killing everything else.
This is often accomplished by interfering with a process which is crucial
to the target organism and missing [or unimportant] in others. A number of
herbicides inhibit specific enzymes in the biosynthesis of one or another
group of essential amino acids (e.g., aa's not synthesized by animals).
However, inhibition of one enzyme in a pathway may have different effects
than inhibition of another - and this is clearly the question Athel was
alluding to. Several groups have considered this problem with regard to
candidate herbicides which inhibit different enzymes in the pathway for
biosynthesis of branched-chain amino acids. In the late 1980's Robert
LaRossa at duPont published a number of papers which used mutants in
Salmonella (as a model organism) to try to unravel why inhibition of one
enzyme, acetohydroxyacid synthase, has particularly strong effects on
cells. It appears that there are at least two issues involved: One is the
possible toxic effect of the build-up of an intermediate when the enzyme
which uses it is inhibited, and the other is the peculiar structure of the
pathway, which uses the same set of enzymes to carry out two different
sets of reactions [i.e., rather than a branch-point where two enzymes
compete for a common intermediate, it has a branch where two candidate
intermediates compete for common enzymes].
We were encouraged by LaRossa and by John Schloss to attempt to go further
with a quantitative analysis of the dynamics of the pathway. Sabine
Epelbaum in our laboratory made extensive measurements in a model system
(an S typhimurium strain) of intracellular levels of enzymes, many
intermediates, etc., under different physiological conditions. The
analysis of the effects of two inhibitors has been published:
Sabine Epelbaum, D.M. Chipman & Z. Barak, (1996) Journal of Bacteriology
178:1187-1196.
As one might expect, a complete analysis doesn't work, because there are
effects we can only guess at, but don't yet have a way to measure. But it
is an interesting example of how the dynamic structure of a metabolic
pathway can lead to non-obvious effects upon inhibiton of individual
enzymes.
If anyone is interested, after looking at this paper, in attempting to
model the system using MCT (or any other method), we would be delighted
to help / collaborate.
- - - - - - - - - - - - - - - - -
David Chipman Chipman at bgumail.bgu.ac.il
Department of Life Sciences Tel: [972]-7-6472 646
Ben-Gurion University Fax: [972]-7-6472 890
Beer-Sheva 84105, ISRAEL
