CCL: W:Computational drug design blues

 Sent to CCL by: "Phil Hultin" []
 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
 -----Original Message-----
 > From: []
 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/]
 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