CCL: Computational drug design blues

["James T Metz" <james.metz%abbott.com>]

CCL Colleagues,
 
 
        Regarding prediction
 of synthetic difficulty, one approach to this problem might involve
 
constructing a descriptor-based QSAR  model
 of compound (catalogue) cost ($Cost/mg) or perhaps log ($Cost/mg).
 
 
        You might end up with
 an equation something like:
 
 
        Log($Cost/mg) = 0.5 *
 # chiral centers + 0.7 # large rings + # spiro-fused centers + ...
 
 
        This idea, of course,
 is based on an assumption that synthetic difficulty roughly equates
 
to economics for thousands of compounds.
  Economics roughly equates to how difficult it is to make the
 molecule.
 
 
        There are of course
 problems with this approach.  One obvious problematic group of
 compounds
 
would be natural products.  Some natural
 products have exquisitely complicated molecular skeletons, yet
 
are obtained relatively inexpensively by
 extraction methods.  So the cost for certain molecules will not
 
reflect synthetic difficulty.  You may (?)
 need to exclude those compounds from your training set.  But, it
 
might be worth trying to build the model several
 different ways.
 
 
        Sources of data are
 plentiful.  Pick up your Aldrich catalogue and you will find plenty of
 structure/cost
 
information.  Probably a good idea to use the
 costs from a single supplier so as not to add further noise (factors)
 
to the analysis.
 
 
        As a check of your
 final model, you might want to make cost predictions for 100 molecules or so.
  Then have 10 
 
synthetic chemist friends rate the difficulty of
 synthesis for each compound on a scale from 1 to 5.  Don't be
 surprised
 
if you get very different (inconsistent) answers.
  You will need to do some statistical averaging here.
 
 
        Not to get
 side-tracked, but regarding the (in)consistency of chemists in judging chemical
 structures, please 
 
see the interesting publication from Lajiness et
 al. "Assessment of Consistency of Medicinal Chemists in Reviewing
 
Sets of Compounds" J. Med. Chem. 47 (2004)
 4891.   An interesting statement from the abstract of this paper is,
 
 
        "It was found
 
that medicinal chemists were not very consistent in the
 compounds they rejected as being
 
undesirable."
 
 
 
        Regards,
 
        Jim Metz
 
        
 
 James T. Metz, Ph.D.
 Abbott Laboratories
 
 
 james.metz%abbott.com