From owner-btk-mca@hgmp.mrc.ac.uk Wed Jan 16 09:01:04 2002 Return-Path: Received: from localhost (localhost [127.0.0.1]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id B428117B73 for ; Wed, 16 Jan 2002 09:01:03 +0000 (GMT) Received: from localhost (localhost [127.0.0.1]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id 606F217B7D for ; Wed, 16 Jan 2002 09:01:01 +0000 (GMT) Received: from niobium.hgmp.mrc.ac.uk (niobium [193.62.192.41]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id 5327117B73 for ; Wed, 16 Jan 2002 09:01:00 +0000 (GMT) Received: (from news@localhost) by niobium.hgmp.mrc.ac.uk (8.9.3+Sun/8.8.8) id JAA03268 for btk-mca-list@hgmp.mrc.ac.uk; Wed, 16 Jan 2002 09:00:39 GMT X-Authentication-Warning: niobium.hgmp.mrc.ac.uk: news set sender to using -f From: athel@ibsm.cnrs-mrs.fr (Athel Cornish-Bowden) X-Newsgroups: bionet.metabolic-reg Subject: Re: Realism in drug discovery Date: 16 Jan 2002 09:00:34 -0000 Organization: BIOSCI/MRC Human Genome Mapping Project Resource Centre Lines: 42 Message-ID: Mime-Version: 1.0 Content-Type: text/plain; charset="us-ascii" X-Complaints-To: news@net.bio.net X-Received: from localhost (localhost [127.0.0.1]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id C233317B7E for ; Wed, 16 Jan 2002 09:00:31 +0000 (GMT) X-Received: from ibsm.cnrs-mrs.fr (ir2cbm.cnrs-mrs.fr [193.50.234.128]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id 58CFC17B7B for ; Wed, 16 Jan 2002 09:00:30 +0000 (GMT) X-Received: from [10.234.32.112] ([10.234.32.112]) by ibsm.cnrs-mrs.fr (8.10.1/jtpda-5.3.3) with ESMTP id g0G8x0003423 for ; Wed, 16 Jan 2002 09:59:00 +0100 X-Sender: cornish@ibsm.cnrs-mrs.fr X-To: btk-mca@hgmp.mrc.ac.uk To: btk-mca@hgmp.mrc.ac.uk Sender: owner-btk-mca@hgmp.mrc.ac.uk Precedence: bulk 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 -- Athel Cornish-Bowden athel@ibsm.cnrs-mrs.fr http://bip.cnrs-mrs.fr/bip10/homepage.htm --- .