From Jeffrey.Gosper@brunel.ac.uk Wed Jan 5 05:47:27 1994 Received: from sirius.brunel.ac.uk for Jeffrey.Gosper@brunel.ac.uk by www.ccl.net (8.6.4/930601.1506) id FAA25256; Wed, 5 Jan 1994 05:16:41 -0500 Received: from molnir.brunel.ac.uk by sirius.brunel.ac.uk with SMTP (PP) id <08579-0@sirius.brunel.ac.uk>; Wed, 5 Jan 1994 10:16:22 +0000 From: Jeffrey J Gosper Message-Id: <6022.9401051016@molnir.brunel.ac.uk> Subject: De Novo drug design To: chemistry@ccl.net Date: Wed, 5 Jan 1994 10:16:07 +0000 (GMT) X-Mailer: ELM [version 2.4 PL21] Mime-Version: 1.0 Content-Type: text/plain; charset=US-ASCII Content-Transfer-Encoding: 7bit Content-Length: 11018 I recently posted a query regarding examples of the De Novo design of drugs. Thanks to all those responding and here is a summary of the comments. P.S. I've cut the repeat replies. ****************************************************************************** The 'classic' example you seek is Mark von Itzstein and Peter Colman's work on neurimidase inhibitors as anti-flu drugs. Their very first do novo inhibitor is in second stage trials and there are much better ones coming along behind. See the recent cover story in Nature. Dr. David A. Winkler Voice: 61-3-542-2244 Principal Research Scientist Fax: 61-3-543-8160 CSIRO Division of Chemicals and Polymers Private Bag 10 Clayton, Australia. ******************************************************************************* Dear Fellow Netters, About two or three years ago, Hoffmann-La Roche of Switzerland brought the first "designed" drug to the market. It is a drug that passes the blood/brain barrier, and is converted by an ezymatic reaction in the brain to the active compound. The pre- drug was modelled for that enzyme. As far as I know, the German chemical and pharmaceutical industries use Molecular Modelling extensively. following their demand, there have been several new position for computational chemistry professors founded during the past five years to teach students the basics of modelling. Our MM software MOBY is equally successful in industry and universities. With the compliments of the season, Dr. Rainer Stumpe Springer-Verlag Chemistry Editorial Tiergartenstr. 17 D-69121 Heidelberg INTERNET:STUMPE@SPINT.COMPUSERVE.COM ******************************************************************************* I read with interest an earlier question requesting info about some drugthat was designed from computational modelling. About two years ago, I asked for "semiempirical success" stories on thsi net and got a rather low response. Given my interest on a variety of fronts, I have been thinking about this for sometime. Please excuse the soapbox, but I would like to share some of my thoughts and those of others I have collected over the past few years on this issue: Drug companies and other chemical manufacturers are not going to tell you about this even if they have an example. This type of stuff is usually proprietary. Is this really the correct question to ask about computational chemistry (CC from here on)? What is it that we expect CC to accomplish for us? Is it going to replace experimental investigations? I look at CC in a company's product discovery cycle as a contributor to the process, not an end in itself. CC will NOT replace experimental information or procedures. We should not tell management (whether scientific or "lay") that it will. We should not try to sell it on this basis. The CC out there now is based on a set of models that are imperfect. These imperfections are present from molecular mechanics through semiempirical to ab initio methods. I admit they are getting better and more reliable (I work quite hard along these lines myself in the area of semiempirical methods) but they will never replace direct observations. How then should CC be viewed? I think an excellent analogy is the way we think about the analytical chemistry (AC) division of any large res- earch operation. AC supports efforts in all phases of the research process. However, the mass spec guy is never asked "What specific drug product is that there $500,000 GC/MS dohicky responsible for?" Everyone recognizes that the mass spec is part of the effort, and things would be crippled without it. This is how CC should be integrated into the research/discovery process. There are several models on how to include CC in a company's effort. In one, the CC guys are a consulting group that works with people that bring them specific problems. In another, each effort has one or more CC guys IN the group. Both are valid and both seem to be producing results. CC is good are predicting trends and in focusing experimental investigations, which are fairly expensive these days. CC should be part of every research problem in a modern setting. PART, I said, not WHOLE. Alot of the recent "backlash" against CC is due to overselling. If we CC folk expect to survive, we don't need to oversell the results that we can provide, but honestly point out what CC should be doing. To finish, I'll tell a little story. When I was interviewing for a job on leaving the Dewar group about 6 years ago, I visited the research labs of a large midwestern polymer manufacturer. I was shown a lab with 4 PhD polymer chemists in it. Each was required to make 1 new polymer blend per week. These blends then went to physical testing for evaluation as new products. The company expected to get one new CANDIDATE for a new product each year out of that lab. Seems a bit cost prohibitive doesn't it? They asked me how CC could help them. Back then, the answer was much less positive than it is now, but even then, CC could have helped them focus their efforts more directly and greatly enhanced the "hit rate." IMHO, that's what we do best. Hope this wasn't too preachy..... Andy Holder ps I welcome comments from others, especially our industrial brethren. Message 4/25 From Andy Holder Page 4 =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-= DR. ANDREW HOLDER Assistant Professor of Computational/Organic Chemistry Department of Chemistry || BITNET Addr: AHOLDER@UMKCVAX1 University of Missouri - Kansas City || Internet Addr: aholder@vax1.umkc.edu Spencer Chemistry, Room 315 || Phone Number: (816) 235-2293 Kansas City, Missouri 64110 || FAX Number: (816) 235-1717 =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-= ******************************************************************************** Hello, There are numerous examples of "designed" compounds that have biological activity. Unfortunately, many companies do not reveal this information. You should consult the December 1993 issue of Scientific American for a well written article by Charlie Bugg et al. Phil Bowen Computational Center for Molecular Structure and Design Department of Chemistry University of Georgia ******************************************************************************* Agouron Pharmaceuticals has published work on de novo design of inhibitors to thymidylate synthase; some of these inhibitors are in clinical trials. Ciba-Geigy and BioCryst have published work on de novo design of inhibitors of purine nucleoside phosphorylase; I think one of these may also be in trials. DuPont-Merck has a paper in press in Science describing their de novo design and crystallographic verification of a potent, nonpeptide HIV protease inhibitor. This compound is also in clinical trials. Jeff Blaney Chiron ******************************************************************************* Certainly all of the HIV-protease inhibitors fit into your category. Abbott has at least one in clinical trial. The big splash was the DuPont-Merck cyclic urea , but SmithKline also designed a similar compound. The former is in the clinic I think; I don't know about the latter. Additionally, the renin inhibitors were designed, usually from modeled structures. Alex Vlodower and John Erickson have a recent review on the HIV protease inhibitors. Yvonne Martin Abbott Laboratories There was also a recent ACS Satellite Symposium on the topic. From MARTIN@CMDA ******************************************************************************* I'm not aware of those that have reached market or clinical trails but, there was a article about the process this year: J.Montgomery, S.Niwas, Structure Based Drug Design, CHEMTECH 23(11) November 1993, 30 Charles G James Chemistry Department University of North Carolina at Asheville. One University Heights Asheville, NC 28804-3299 Phone: 704-251-6443 james@unca.edu ******************************************************************************** There are a few examples which come close to being De novo designed, but I've olny heard these discussed at conferences (even these used a large amount of physical data in the models). A recent scientific american article should leed you in the right direction. Scientific American December 1993 Drugs by Design 92-98 C.E.Bugg W.M.Carson J.A.Montgomery Regards, Mike Miller ******************************************************************************* In the December 1993 issue of Scientific American, p.92 there is a good article "Drugs by Design." At the end of the article, p. 98, there are listed some drugs that were designed. I know that Agrouon's molecules are in Phase I trials, one in England and one in the States. They were developed from the tertiary structure of the enzyme in question. ******************************************************************************