Subject: De Novo drug design

From: Jeffrey J Gosper <[email-masked]>
Date: Wed, 5 Jan 1994 10:16:07 +0000 (GMT)

I recently posted a query regarding  examples of the De Novo design of drugs.
Thanks to all those responding and here is a summary of the comments. 

P.S. I've cut the repeat replies.

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The 'classic' example you 
seek is Mark von Itzstein and Peter Colman's work on neurimidase inhibitors as 
anti-flu drugs.  Their very first do novo inhibitor is in second stage trials 
and there are much better ones coming along behind.  See the recent cover story 
in Nature.                                                                

   Dr. David A. Winkler                        Voice: 61-3-542-2244      
   Principal Research Scientist                Fax:   61-3-543-8160      
   CSIRO Division of Chemicals and Polymers                              
   Private Bag 10                                                        
   Clayton, Australia.                                                   
                                      
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Dear Fellow Netters,

About two or three years ago, Hoffmann-La Roche of Switzerland
brought the first "designed" drug to the market. It is a drug
that passes the blood/brain barrier, and is converted by an
ezymatic reaction in the brain to the active compound. The pre-
drug was modelled for that enzyme.

As far as I know, the German chemical and pharmaceutical
industries use Molecular Modelling extensively. following their 
demand, there have been several new position for computational 
chemistry professors founded during the past five years to teach          
students the basics of modelling.                                         
Our MM software MOBY is equally successful in industry and universities.  
                                                                          
With the compliments of the season,                                       
                                                                          
Dr. Rainer Stumpe                                                         
Springer-Verlag                                                           
Chemistry Editorial                                                       
Tiergartenstr. 17                                                         
D-69121 Heidelberg                                                        
INTERNET:[email-masked]               

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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.   
 
Message 4/25  From Andy Holder                                            Page 4

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                              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]
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Hello,

    There are numerous examples of "designed" compounds that have biological
activity.  Unfortunately, many companies do not reveal this information. 
You should consult the December 1993 issue of Scientific American for a
well written article by Charlie Bugg et al.

Phil Bowen
Computational Center for Molecular Structure and Design
Department of Chemistry
University of Georgia

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Agouron Pharmaceuticals has published work on de novo design of inhibitors
to thymidylate synthase; some of these inhibitors are in clinical trials.

Ciba-Geigy and BioCryst have published work on de novo design of inhibitors
of purine nucleoside phosphorylase; I think one of these may also be in
trials.

DuPont-Merck has a paper in press in Science describing their de novo
design and crystallographic verification of a potent, nonpeptide HIV protease
inhibitor.  This compound is also in clinical trials.

Jeff Blaney
Chiron

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Certainly all of the HIV-protease inhibitors fit into your category.  Abbott has
at least one in clinical trial.  The big splash was the DuPont-Merck cyclic urea
, but SmithKline also designed a similar compound.  The former is in the clinic
I think; I don't know about the latter.

Additionally, the renin inhibitors were designed, usually from modeled structures.

Alex Vlodower and John Erickson have a recent review on the HIV protease inhibitors.

Yvonne Martin
Abbott Laboratories

There was also a recent ACS Satellite Symposium on the topic.

>From MARTIN@CMDA

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I'm not aware of those that have reached market or clinical trails but,
there was a article about the process this year:

J.Montgomery, S.Niwas, Structure Based Drug Design, CHEMTECH 23(11) November
1993, 30

Charles G James                                                           
Chemistry Department                                                      
University of North Carolina at Asheville.                               
One University Heights                                                   
Asheville, NC 28804-3299                                                 
                                                                         
Phone: 704-251-6443                                                      
                                                                         
[email-masked]             

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        There are a few examples which come close to being 
De novo designed, but I've olny heard these discussed at conferences
(even these used a large amount of physical data in the models).  A recent
scientific american article should leed you in the right direction.

  Scientific American December 1993 Drugs by Design 92-98
  C.E.Bugg W.M.Carson J.A.Montgomery

Regards,
Mike Miller

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In the December 1993 issue of Scientific American, p.92 there is a good article 
"Drugs by Design." At the end of the article, p. 98, there are listed some
drugs that were designed. I know that Agrouon's molecules are in Phase I
trials, one in England and one in the States. They were developed from the
tertiary structure of the enzyme in question.

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