From owner-chemistry: at :ccl.net Wed Sep 14 18:28:49 2005 From: "CCL" To: CCL Subject: CCL: Computational drug design blues Message-Id: <-29162-050914182335-30953-2NbaQmdzjXHCm+8GjNpz2w]-[server.ccl.net> X-Original-From: "Phil Hultin" Content-Transfer-Encoding: 7bit Content-Type: text/plain; charset="us-ascii" Date: Wed, 14 Sep 2005 17:23:25 -0500 MIME-Version: 1.0 Sent to CCL by: "Phil Hultin" [hultin]-[cc.umanitoba.ca] I note that the question of assessing the "ease of synthesis" has excited a fair bit of comment. As I already pointed out, and as also stated by Gary Breton, the organic chemistry community does not think it is actually possible to meaningfully assess "ease of synthesis" by an algorithmic approach. To those who have mentioned various computer-aided synthesis planning software, let me simply ask: once you have a proposed synthetic route, how do you determine whether it is "easy" to put into practice or not? There have been many programs developed to seek synthetic pathways, but none has actually been able to differentiate unambiguously or consistently between "good" options and "bad" options. The number of steps or the average yield per step are not meaningful criteria in and of themselves, although they do enter into the assessment. Other issues that bear on the practicality question are (not a comprehensive list): > cost of raw materials > cost of solvents > cost of reagents, catalysts etc. > cost of disposal of waste materials > health and lab safety hazards associated with reagents, solvents and intermediate compounds > level of selectivity actually attainable (stereoselectivity, regioselectivity, chemoselectivity) > need for purification, particularly chromatography > solubilities, boiling points and other physical parameters > expected thermodynamic and kinetic stability of intermediates > scalability - can the proposed route be used only for milligram amounts or can it be implemented on gram or kilo scales as needed? The list could go on. The bottom line is that in order to determine whether a proposed drug candidate is actually practical, you need to consider numerous variables that cannot be reduced to a simple numerical scale. This is where the experience and expertise of the bench chemist is essential. Dr. Philip G. Hultin Associate Professor of Chemistry, University of Manitoba Winnipeg, MB R3T 2N2 hultin]-[cc.umanitoba.ca http://umanitoba.ca/chemistry/people/hultin -----Original Message----- > From: owner-chemistry]-[ccl.net [mailto:owner-chemistry]-[ccl.net] Sent: September 14, 2005 1:44 PM To: Hultin, Philip G. Subject: CCL: W:Computational drug design blues Sent to CCL by: Gary Breton [gbreton]"[berry.edu] Speaking as an organic chemist I can tell you that the answer to your question is probably no. There is no easy way to tell whether a given compound is easy or difficult to synthesize other than to give it to a medicinal or organic chemist that has experience in and knows synthesis. For example, a compound with a nitro group at one position may be very easy to synthesize, but move it over one carbon and suddenly you have a very difficult system to synthesize. Any "simple" guidelines would probably not differentiate between the difficulty in synthesis of these types of isomers. While there have been attempts at generating software to aid in "deconstructing" molecules towards the goal of making planned syntheses easier, none of these (at least to my knowledge) is particular robust. I have never heard of an organic chemist...or seen cited in a paper...the use of such software to aid in a synthetic route. While there may be exceptions, it certainly isn't the norm. ..and I don't say all this just for the sake of job security ;) Gary W. Breton Associate Professor Hard-Working Organic Chemist Department of Chemistry Berry College PO Box 495016 Mount Berry, GA 30149 > Sent to CCL by: "Sandeep Kumar" [kumarsan\a/jhu.edu] > Dear CCLers: > > I need some advice about the drug discovery/design. Using structure based > design, one could develope several potential small molecular inhibitors/drugs > for a given protein target. Many of these compounds may appear very attractive > as they satisfy all lipinski's rules and your requirements for > selectivity/specificity and may even have desirable solubility/ADME profiles. > These days its possible to incorporate all these features right at the > computational design stage. However, the organic synthesis of the compound > still remains a bottleneck as it turns out that many of the designed compounds > are 'hard' to synthesize or may require many steps of synthesis. I was > wondering if there are some simple guidelines in the form of literature or > 'hands on' experience available which could tell the computational/medicinal > chemist whether a designed compound would be easy or hard to synthesize before > he/she talks to the organic chemist. > > All your responses are greatly appreciated. > > Yours sincerely > Sandeep Kumar, Ph.D. > Johns Hopkins University, > Dept. of Biology, > 106 Mudd Hall, > 3400 N. Charles St. > Baltimore, MD 21218. > Phone: 410-516-8433 > Email: kumarsan]-[jhu.edu