CCL: Computational drug design blues

 Sent to CCL by: "Phil Hultin" [hultin]-[]
 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
 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
 -----Original Message-----
 > From: owner-chemistry]-[ [mailto:owner-chemistry]-[]
 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]"[]
 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
 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/]
 > Dear CCLers:
 > I need some advice about the drug discovery/design. Using structure based
 > design, one could develope several potential small molecular
 > for a given protein target. Many of these compounds may appear very
 > as they satisfy all lipinski's rules and your requirements for
 > selectivity/specificity and may even have desirable solubility/ADME
 > 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
 > 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
 > chemist whether a designed compound would be easy or hard to synthesize
 > 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]-[