From owner-btk-mca@hgmp.mrc.ac.uk Wed Jan 16 10:01:07 2002 Return-Path: Received: from localhost (localhost [127.0.0.1]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id C043117B8A for ; Wed, 16 Jan 2002 10:01:05 +0000 (GMT) Received: from localhost (localhost [127.0.0.1]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id 295B717B83 for ; Wed, 16 Jan 2002 10:01:02 +0000 (GMT) Received: from niobium.hgmp.mrc.ac.uk (niobium [193.62.192.41]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id 9392717B7B for ; Wed, 16 Jan 2002 10:01:00 +0000 (GMT) Received: (from news@localhost) by niobium.hgmp.mrc.ac.uk (8.9.3+Sun/8.8.8) id JAA03675 for btk-mca-list@hgmp.mrc.ac.uk; Wed, 16 Jan 2002 09:54:06 GMT X-Authentication-Warning: niobium.hgmp.mrc.ac.uk: news set sender to using -f From: dfell@brookes.ac.uk (David Fell) X-Newsgroups: bionet.metabolic-reg Subject: Re: Realism in drug discovery Date: 16 Jan 2002 09:54:04 -0000 Organization: BIOSCI/MRC Human Genome Mapping Project Resource Centre Lines: 38 Message-ID: <5.1.0.14.0.20020116094318.02823580@csmail.brookes.ac.uk> References: <5.1.0.14.0.20020115235050.01b349b0@csmail.brookes.ac.uk> <5.1.0.14.0.20020115235050.01b349b0@csmail.brookes.ac.uk> Mime-Version: 1.0 Content-Type: text/plain; charset="us-ascii"; format=flowed 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 26B3617B84 for ; Wed, 16 Jan 2002 09:54:01 +0000 (GMT) X-Received: from brookes.ac.uk (csmail.brookes.ac.uk [161.73.1.1]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id 19A2317B86 for ; Wed, 16 Jan 2002 09:53:59 +0000 (GMT) X-Received: from ta4cc1e4.brookes.ac.uk (ta4cc1e4.brookes.ac.uk [161.73.151.110]) by brookes.ac.uk (8.11.1/8.11.1) with ESMTP id g0G9sS001933 for ; Wed, 16 Jan 2002 09:54:28 GMT X-Sender: p0054633@csmail.brookes.ac.uk X-Mailer: QUALCOMM Windows Eudora Version 5.1 X-To: btk-mca@hgmp.mrc.ac.uk X-In-Reply-To: To: btk-mca@hgmp.mrc.ac.uk Sender: owner-btk-mca@hgmp.mrc.ac.uk Precedence: bulk At 13:13 16/01/02 +1000, Len Pattenden wrote: >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. An example is the comparison between the action of the potential drug 5-deazaacyclotetrahydrofolate on its target, the enzyme glycinamide ribonucleotide transformylase (of purine biosynthesis) and its impact on the flux of de novo purine biosynthesis in a human T-cell leukaemia line. (G K Smith et al in 'Control of Metabolic Processes ' ed A Cornish-Bowden & M-L Cardenas, Plenum Press, 1990. Because of the low flux control coefficient of this enzyme (0.01), the IC50 on the enzyme activity is very much lower than the IC50 on the flux. Nevertheless, you can eventually get substantial inhibition of the flux - though by that time the enzyme is only 2% active and the intracellular drug level is 10 times the concentration needed to produce an equivalent inhibition of the enzyme. The enzyme is still being studied as a potential drug target. I've got a Power Point slide of this data - I need to think about how to make the graph available to the newsgroup Athel is right that the flux control coefficient itself is not sufficient to predict all this behaviour, though low values do correlate with significant differences between the in vitro effect on the enzyme and the effect on in vivo flux. The flux control coefficient of glycinamide ribonucleotide transformylase was estimated at 0.01. My guess is that it is still a better target than a feedback-inhibited enzyme with an equivalent flux control coefficient. David ========================================================= Prof David Fell, School of Biological & Molecular Sciences, Oxford Brookes University, Oxford OX3 0BP, UK Tel. +44 (0)1865 483247 FAX +44 (0)1865 484017 Mob: +44 (0)7786 515729 http://mudshark.brookes.ac.uk/ --- .