From owner-chemistry -x- at -x- ccl.net Wed Sep 14 13:44:14 2005 From: "CCL" To: CCL Subject: CCL: W:Computational drug design blues Message-Id: <-29151-050914112552-8391-2NbaQmdzjXHCm+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 09:40:53 -0500 MIME-Version: 1.0 Sent to CCL by: "Phil Hultin" [hultin=-=cc.umanitoba.ca] This question about the synthetic feasibility of a computationally-selected drug candidate is a very good one, but unfortunately there is not a nice simple answer. To decide whether a structure is synthetically accessible, the only way that I can think of is to actually know organic chemistry. It is usually pretty straightforward to identify things that are "hard" to make based on relatively elementary knowledge of reactions. It is NOT straightforward to decide whether something is "easy" to make, however - at least not for molecules of any complexity. I would suggest that any computational drug designer should consider a refresher course in organic chemistry, followed by a basic introduction to the design of organic syntheses such as Stuart Warren's book "Organic Synthesis: the disconnection approach". In a computation, we generally believe that things are deterministic and thus that a single result (within round-off error) should be obtained from a fixed starting point. In synthesis, there is no single answer to the question of how to synthesize a given target. Moreover, the number of permutations grows exponentially (at least) as the size of the target grows. Thus, there is a qualitative element to determining whether something is feasible or not. Of course, I am quite aware that there is a qualitative and creative element to computational chemistry too and I do not mean to put down computational people in any way, or to set organickers up on a pedestal. 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 9:10 AM To: Hultin, Philip G. Subject: CCL: W:Computational drug design blues 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