Len Pattenden wrote:
>David your comments are very interesting and when first reading the FAQ
>for this group it also makes a mention of this, however I have never read
>*how* MCA can be used in drug design and it kinda escapes me. Perhaps this
>is a simple thing to point out. Perhaps someone's done it? Is your thought
>the system level impact of a drug? How exactly do you go about doing this?
>Good question, and one that we've tended to be a bit vague in answering. If
you mean how do the tools of metabolic control analysis (control
coefficients, elasticities, etc.) help in designing drugs, then I suspect
the answer is "not much", though there are certainly those who argue that
knowing which enzymes have the highest flux control coefficients gives a
guide as to which enzymes you need to hit with inhibitors or activators. My
feeling is that that is a bit optimistic and that in practice you will
always need to do some computer simulation to get a clear idea of what will
happen if you vary the activity of an enzyme.
Nonetheless, if the question refers more to the philosophy of metabolic
control analysis than to its nuts and bolts then I continue to think it
very important for drug design, because it forces you to start thinking in
systemic terms; only by focussing on the whole system can you begin to
grasp what pharmacology is all about.
Getting back to the nuts and bolts, I think the first paper that made a
serious attempt to translate metabolic control analysis into practical
biotechnology was that of Hans Westerhoff and Douglas Kell in Biotechnol.
Bioeng. 30, 101-107 (1987). However, it's not especially light reading (you
won't want to read it in bed), and you may find a modelling-based
discussion (such as ours in Bioorg. Chem. 23, 439-449 (1995)) a gentler
introduction.
athel
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Athel Cornish-Bowden
athel at ibsm.cnrs-mrs.frhttp://bip.cnrs-mrs.fr/bip10/homepage.htm
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