From owner-btk-mca@hgmp.mrc.ac.uk Thu Jan 10 02:00:12 2002 Return-Path: Received: from localhost (localhost [127.0.0.1]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id 9889717B04 for ; Thu, 10 Jan 2002 02:00:11 +0000 (GMT) Received: from localhost (localhost [127.0.0.1]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id 44E3F17AB6 for ; Thu, 10 Jan 2002 02:00:08 +0000 (GMT) Received: from niobium.hgmp.mrc.ac.uk (niobium [193.62.192.41]) by mercury.hgmp.mrc.ac.uk (Postfix) with ESMTP id 5B3D817AED for ; Thu, 10 Jan 2002 02:00:06 +0000 (GMT) Received: (from news@localhost) by niobium.hgmp.mrc.ac.uk (8.9.3+Sun/8.8.8) id BAA10476 for btk-mca-list@hgmp.mrc.ac.uk; Thu, 10 Jan 2002 01:54:24 GMT X-Authentication-Warning: niobium.hgmp.mrc.ac.uk: news set sender to using -f From: Len Pattenden X-Newsgroups: bionet.metabolic-reg Subject: Re: Realism in drug discovery Date: Thu, 10 Jan 2002 11:54:20 +1000 Organization: University of Queensland Lines: 64 Message-ID: References: Mime-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII X-Complaints-To: news@uq.edu.au X-Sender: In-Reply-To: To: btk-mca@hgmp.mrc.ac.uk Sender: owner-btk-mca@hgmp.mrc.ac.uk Precedence: bulk G'day Athel; On 9 Jan 2002, Athel Cornish-Bowden wrote: [...] > Most of the top companies are not generating in-house the new products > needed to sustain [their] rates of growth" [...] Drug design, as it is, is a falicy and this is why the pharm industries have problems. They are far too big now and swallowing each other up to try and buy a profit because they cannot produce enough actual new product onto the market that are effective. They must grow at a massive rate to remain viable and so sadly the new pharmaceuticals are underdeveloped in an attempt to get something onto the market and turn some profit. In the "journal" Drug Discovery Today (which is an interesting rag that helps keep lazy literature readers abreast of broad changes and discoveries), they make these facts painfully obvious. The more times you make a virtual library and bias it with experimental designs, the more you find your "active" compounds are lipophilic messes, as these things are more orally and cellularly bioavailable. This is why small companies are springing up using "sugar chemistry" etc, they're changing the scaffolds. If someone can come up with a good liposomal delivery system or somesuch, suddenly peptides and substrates are viable drug candidates - and then it will be open slather. The problem with this is patentability. Who patents a substrate? Can you even do it? So alternate "out-there" therapies are being looked at. Things like proteins as therapeutics, antisense phosphoamidate nucleotides, peptide nucleic acids etc etc. My thought is it will be the ballsy little company that doesn't care about patenting that will make millions in the future selling peptides as therapeutics. Peptides have been evolutionarily selected over eons of times and under conditions we can only guess at but cannot fathom - how small minded is it to assume we can make molecules to do better? Then, of course you have the issue of "the system". Things existing in compartments or interacting in different ways within different environments makes the whole process of drug design a joke. > The conclusion is more optimistic: "Genomics will deliver in the end", but > there isn't actually much offered in the way of evidence to justify this > optimism. Wishful thinking rules, as always. I think genomics can only ever be part of the answer. It's a quick solution to a complex question, but is it correct? Take G-proteins for example. If you try and pump up the expression levels or control the expression, you find your cells die, so you cannot easily use a microarray to see what is switched on and elucidate the pathway. The expression is normally so tightly regulated that it is an amassing of certain proteins (in different locations) that is actually important. Perhaps the genes aren't upregulated at all! Perhaps even proteomics will only tell us part of the answer, or maybe Rodbell was right in 1991 when he said "Nature cannot simply be fathomed by knowing its chemical and physical composition. The living process has evolved far beyond our knowledge of physics and chemistry. Understanding the organization and integration of all cellular information processing systems presents challenges that certainly will not be met in my lifetime, and perhaps never." Len... .