Subject: De Novo Drug design

From: Andy Holder <[email-masked]>
Date: Fri, 17 Dec 1993 17:03:10 -0600 (CST)

Hi Netters!

I read with interest an earlier question requesting info about some 
drugthat was designed from computational modelling.  About two years 
ago, I asked for "semiempirical success" stories on thsi net and got a 
rather low response.  Given my interest on a variety of fronts, I have 
been thinking about this for sometime.  Please excuse the soapbox, but I 
would like to share some of my thoughts and those of others I have 
collected over the past few years on this issue:

  Drug companies and other chemical manufacturers are not going to 
tell you about this even if they have an example.  This type of stuff is 
usually proprietary.

  Is this really the correct question to ask about computational 
chemistry (CC from here on)?  What is it that we expect CC to accomplish 
for us?  Is it going to replace experimental investigations?

  I look at CC in a company's product discovery cycle as a contributor to 
the process, not an end in itself.  CC will NOT replace experimental 
information or procedures.  We should not tell management (whether 
scientific or "lay") that it will.  We should not try to sell it on 
this basis.  The CC out there now is based on a set of models that are 
imperfect.  These imperfections are present from molecular mechanics 
through semiempirical to ab initio methods.  I admit they are getting 
better and more reliable (I work quite hard along these lines myself in 
the area of semiempirical methods) but they will never replace direct 
observations.

  How then should CC be viewed?  I think an excellent analogy is the way 
we think about the analytical chemistry (AC) division of any large res-
earch operation.   AC supports efforts in all phases of the research 
process.  However, the mass spec guy is never asked "What specific drug 
product is that there $500,000 GC/MS dohicky responsible for?"  Everyone
recognizes that the mass spec is part of the effort, and things would be 
crippled without it.

  This is how CC should be integrated into the research/discovery process. 
There are several models on how to include CC in a company's effort.  In 
one, the CC guys are a consulting group that works with people that 
bring them specific problems.  In another, each effort has one or more 
CC guys IN the group.  Both are valid and both seem to be producing 
results.  CC is good are predicting trends and in focusing experimental
investigations, which are fairly expensive these days.  CC should be 
part of every research problem in a modern setting.  PART, I said, not 
WHOLE.

  Alot of the recent "backlash" against CC is due to overselling.  If
we CC folk expect to survive, we don't need to oversell the results that 
we can provide, but honestly point out what CC should be doing.

  To finish, I'll tell a little story.  When I was interviewing for a 
job on leaving the Dewar group about 6 years ago, I visited the research 
labs of a large midwestern polymer manufacturer.  I was shown a lab with 
4 PhD polymer chemists in it.  Each was required to make 1 new polymer 
blend per week.  These blends then went to physical testing for 
evaluation as new products.  The company expected to get one new 
CANDIDATE for a new product each year out of that lab.  Seems a bit
cost prohibitive doesn't it?  They asked me how CC could help them.
Back then, the answer was much less positive than it is now, but even 
then, CC could have helped them focus their efforts more directly and
greatly enhanced the "hit rate."  IMHO, that's what we do best.

  Hope this wasn't too preachy.....

   Andy Holder

ps  I welcome comments from others, especially our industrial brethren.

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=
                              DR. ANDREW HOLDER
             Assistant Professor of Computational/Organic Chemistry

Department of Chemistry              ||  BITNET Addr:   AHOLDER@UMKCVAX1
University of Missouri - Kansas City ||  Internet Addr: [email-masked]
Spencer Chemistry, Room 315          ||  Phone Number:  (816) 235-2293
Kansas City, Missouri 64110          ||  FAX Number:    (816) 235-1717
=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=