From owner-btk-mca@hgmp.mrc.ac.uk Wed Jan 16 10:46:15 2002 Return-Path: Received: from localhost (localhost [127.0.0.1]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id 076D717B86 for ; Wed, 16 Jan 2002 10:46:09 +0000 (GMT) Received: from localhost (localhost [127.0.0.1]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id BCE5B17B8A for ; Wed, 16 Jan 2002 10:46:02 +0000 (GMT) Received: from niobium.hgmp.mrc.ac.uk (niobium [193.62.192.41]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id 9070517AED for ; Wed, 16 Jan 2002 10:46:00 +0000 (GMT) Received: (from news@localhost) by niobium.hgmp.mrc.ac.uk (8.9.3+Sun/8.8.8) id KAA04475 for btk-mca-list@hgmp.mrc.ac.uk; Wed, 16 Jan 2002 10:32:35 GMT X-Authentication-Warning: niobium.hgmp.mrc.ac.uk: news set sender to using -f From: dbk@aber.ac.uk ("Douglas Kell") X-Newsgroups: bionet.metabolic-reg Subject: Re: Realism in drug discovery - and how to get there Date: 16 Jan 2002 10:32:34 -0000 Organization: BIOSCI/MRC Human Genome Mapping Project Resource Centre Lines: 109 Message-ID: <3C4556BC.22020.3D6D0F35@localhost> References: Mime-Version: 1.0 Content-Type: text/plain; charset=US-ASCII Content-Transfer-Encoding: 7BIT 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 AB5E617B91 for ; Wed, 16 Jan 2002 10:32:31 +0000 (GMT) X-Received: from braint.aber.ac.uk (braint.aber.ac.uk [144.124.16.42]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id E8ADF17B90 for ; Wed, 16 Jan 2002 10:32:29 +0000 (GMT) X-Received: from pcbdad.dbs.aber.ac.uk ([144.124.113.30] helo=aardvark) by braint.aber.ac.uk with esmtp (Exim 3.21 #1) id 16QnMq-0003mb-00; Wed, 16 Jan 2002 10:32:28 +0000 X-To: btk-mca@hgmp.mrc.ac.uk X-Reply-To: dbk@aber.ac.uk X-Cc: athel@ibsm.cnrs-mrs.fr (Athel Cornish-Bowden) X-Priority: normal X-In-reply-to: X-Mailer: Pegasus Mail for Win32 (v3.12c) To: btk-mca@hgmp.mrc.ac.uk Sender: owner-btk-mca@hgmp.mrc.ac.uk Precedence: bulk I'd agree with Athel apropos the motivations for believing that MCA has significance in identifying targets, but that full modelling is required to do it properly (where levels of inhibition are high and so changes are far from infinitesial), and thanks for the kind plug for our paper. I definitely and equally agree that the Hans and dbk paper referred to below is *not* light reading, but we did 2 parallel ones that were intended for a more general audience. The second was not allowed (by Tibtech) to have any formal equations at all.... Kell, D. B. and H. V. Westerhoff (1986). "Metabolic control theory: its role in microbiology and biotechnology." FEMS Microbiol. Rev. 39: 305-320. Kell, D. B. and H. V. Westerhoff (1986). "Towards a rational approach to the optimization of flux in microbial biotransformations." Trends Biotechnol. 4: 137-142. In drug discovery the trend is now *very much* towards a more systems approach, partly driven by post-genomics (where we purportedly know all the biochemical players and can't ignore them any more) and partly because a lot of drugs fail between the lead stage/first phase and getting out of the door. This is called 'attrition' in Pharma- speak and runs at ca 85-90% (or more) in *all* the big Pharma I know about, at ruinous expense. The 2 main reasons are (i) lack of efficacy (doesn't actually work in the rat/person, even if it did on the receptor), (ii) because of pharmacological properties/ toxicity. Each of these counts as 'unintended efects elsewhere in the system'. The conclusion is obvious. A small plug if I may. I am program chair of the Society for Biomolecular Screening meeting this year (Sept 23-26, The Hague, NL) http://www.sbsonline.org/ and as you will see the theme is EXACTLY 'high information content screening' whose broad aim is to help address these issues. Colleagues in the newsgroup are invited to submit papers/posters to this. It is very much the premier non- commercially-run forum for Drug Discovery, last year's event in Baltimore attracting ca 2,500 delegates. All the best, Douglas. On 16 Jan 2002, at 9:00, Athel Cornish-Bowden wrote: From: athel@ibsm.cnrs-mrs.fr (Athel Cornish-Bowden) Subject: Re: Realism in drug discovery Date sent: 16 Jan 2002 09:00:34 -0000 Organization: BIOSCI/MRC Human Genome Mapping Project Resource Centre Originally to: btk-mca@hgmp.mrc.ac.uk To: btk-mca@hgmp.mrc.ac.uk > 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 > > > > --- > > ******************************************************************** *(Prof.) Douglas B. Kell Phone: +44 1970 622334 * *Director of Research * *Institute of Biological Sciences Fax: +44 1970 622354 * *Cledwyn Building * *University of Wales, Email: dbk@aber.ac.uk * *Aberystwyth SY23 3DD, U.K. http://qbab.aber.ac.uk/ * * http://www.abergc.com/* ******************************************************************** ******************************************************************** --- .