Subject: Re: Drug Design

From: Steven Schafer <[email-masked]>
Date: Fri, 24 Mar 1995 10:39:34 -0500 (EST)

I posted a week or so ago that I would send the summary of responses 
to anyone who wanted it insteasd of posting it to the net.  Well, I 
intended to save bandwidth but have recieved over 500 requests.  I have 
sent out a few of the summaries but I can not do 500.  My appologies to 
anyone who I have not gotten it to and to those who may be ticked that I 
am going to now post it here.  Anyways here it is:

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A book chapter entitled "Successes of Computer-Assisted Molecular DEsign" by
Don Boyd, previously of Eli Lilly and Co. is chapter 10 in Reviews of
Computational Chemistry, Volume 1, pp355, 1990. It lists several drugs etc.
that have been designed with the aid of computational methods.

=============================================================================

From the archives,

By the way, the first success in comp.-aided molecular modeling in Japan
might be ACE inhibitor from Takeda. They developed CV-3317(?), that is
in market now, and they analized usign extended huckle. And they found
7-membered ring is very much stable and suitable conformer. Then they
developed 7-membered ring derivatives. Among them, CV-597X(?) was
chosen. After that I do not know. Please ask Dr.Kamiya(Takeda).
And Sankyo researchers developed gastrin antagonist using gastrin
as a template about 10 years ago. I do not well about this. I am sorry.
I searched and found the literatures. They only reported the compounds.
K.Itoh et al., Chem.Pharm.Bull.,34,1128,2078,3747(1986).
He presented only at the symposium about calculations.
He used MM2 and extended Huckel to calculate CV3317 and cyclic
compounds. They took X-ray structure of CV-3317, and found that the
methyl group and indane ring is very near. Thus, he calculated
6-membered ring as 54kcal/mol, 7-membered ring as 0.8kcal/mol, 8-
as 0.7, and 9- as -0.4. And at last they found CV-5975.

     ____/   ___/  ___/ Yoshihisa INOUE (^_^)   the Green Cross Corp.
    /       /     /     2-25-1 Shodai-Ohtani,Hirakata,Osaka 573 JAPAN
   / _ /   /     /         tel: +81-720-56-9328
  /   /   /     /          fax: +81-720-68-9597
_____/ ____/ ____/      E-mail: [email-masked]

========================================================
     Gange, D. M., S. Donovan, and K. Henegar
     "The Design of Insecticidal Uncouplers."
     207th American Chemical Society National Meeting, San Diego, Calif., 
     March 13-17, 1994
     COMP 171
     
     The discovery of the potent insecticide pyrrolomycin in 1985 led to an 
     intensive study of the properties pf pyrrolomycin and related pyrrole 
     insecticides.  Mitochondrial assays indicated that the mode of action 
     of the pyrroles was uncoupling.  The compounds uncouple respiration 
     from phosphorylation, preventing the synthesis of ATP.  A QSAR model 
     describing the activity of the pyrroles has been developed.  The 
     development of the model and the use of the model to predict the 
     activity of a new class of uncouplers will be discussed.
      To contact the lead author, please send email to 
     [email-masked]
     
     --David Saari                              [email-masked]

=========================================================

     One of the research scientists here at the American Cyanamid Company 
     Agricultural Research Division successfully predicted the biological 
     activity of a series of potentially commercial agrochemical compounds. 
     I don't know how much of this research has been cleared for release to 
     the public so I can't give details without checking to see if the 
     research has been published or disclosed at a scientific meeting, 
     etc., (patentability considerations, you know).  In this case, I can 
     say that the research was not a "black box" situation.  The 
     computational chemistry was a tool for predicting possible activity.  
     Nevertheless, chemists did have to make the compounds, and our 
     screening people had to run the tests to confirm biological activity.
     
     --David Saari                        [email-masked]

******************************************************************************

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                        [email-masked]      
                                      
*******************************************************************************

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.                                         
                                                                          
Dr. Rainer Stumpe                                                         
INTERNET:[email-masked]               

*******************************************************************************

........

  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.
                                                                          
..........

  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.
...........

   Andy Holder
University of Missouri - Kansas City ||  Internet Addr: [email-masked]

********************************************************************************

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

*******************************************************************************

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

******************************************************************************* 

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   

*******************************************************************************

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]             

********************************************************************************

        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

*******************************************************************************

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.

******************************************************************************

> Hello,
> 
> 	A while back someone asked about success stories in rational
> drug design.  In that light, what does the group think of the Merck
> groups article in *Science* 23:380-384 where they rationally designed
> inhibitors of HIV protease?
> 
> Martin J. Gallagher	    phone:   (617) 432-1729	  
> Dept. of Neurobiology	    fax:     (617) 734-7557	  
> Harvard Medical School	    E-mail:  [email-masked]

Background information: here at Washington University we developed a 3D-QSAR -
CoMFA model for 59 HIV-protease inhibitors (see J Med Chem 36:4152-4160 1993) -
a model that was based on experimentally derived alignment rules (crystals of 7
inhibitors) and was tested for predictive power (36 compounds with different
chemistry - but peptides as the other 59) and explanatory power (CoMFA fields
were compared and interpreted in the light of binding site residues in immediate
contact with the inhibitors). The work on predictive power was submitted to J 
Med
Chem, and the one on explanatory power is to be printed in Drug Design and
Discovery. 
..........

The non-peptide cyclic ureas were announced at the Gordon Conference in QSAR
(August 1993) where Dr Eyermann gave a lecture (no activities, though). The four
compounds with published activities were predicted by our model as follows (see
the Science paper for #s): 

Cmpd			Actual		Predicted (both as IC50, micromolar)
1			0.63		0.132
2			0.30		0.140
3			0.22		0.23
4			0.036		0.061

..........

Comments regarding the drug design tactics used by the DuPont-Merck group
(or how did they 'set forth' to get advantages in the HIV-protease front):

structural knowledge of the free enzyme and the inhibitor-bound enzyme was
ESSENTIAL for this study, because specific targets were aimed at: 
* atoms in the binding site which were important in the economy of binding which 
were used to define the 
* 3D pharmacophore (exact location of binding site atoms - which are then used
as template for putative structures that can match this pattern), 
which was then used as a query in a
* 3D database search (useful concept: has anyone done such a compound before? -
... or how close to our 3D pattern are already-made-cmpds ?)
this proves many times to be of help, but users are aware that such a method
would not suggest NEW compounds, and this is where the molecular modeler (or 
was it a medicinal chemist?) uses knowledge blended with imagination to come 
with
the
* "_initial_idea_ for a nonpetide inhibitor that includes a structural water
mimic"  (exact quote) - this suggests that someone in the group came with this
suggestion, upon which the work was continued
later on, the skeleton was refined to ensure 
* better complementarity with the 3D pharmacophore
(e.g., two hydroxyls instead of one, to bind two aspartates in the catalytic 
site, and the urea instead of the keto to improve electrostatic negative
pattern in the flaps region for better hydrogen bonding)

..........

The Science paper proves that current concepts used in drug design are valid -
but it is quite clear that a scientist (or a team of scientists) is needed,
because this problem was not solved entirely by a computer. However, the use of
computational methods was essential. 

                                                     ==========================
  Tudor-Ionel Oprea                                  = Tel. (1-314) 935 4672  =
   [email-masked]  =

===============================================================

I don't have the results of the previous survey, but a few examples.
All of these are in the clinic (or were).  Not in any particular order.

1. the Agouron thymidilate synthase inhibitors 
2. the Abbott C2 symmetric HIV protease inhibitors
3. the Biocryst/Ciba/Cornell PNP inhibitors
4. the Dupont-Merck HIV protease inhibitors
5. the Merck carbonic anhydrase inhibitor (will be on the market this year!)
  
Finally, our HIV protease inhibitor, VX-478, should be in the clinic
later this year.

Hope this helps.

/ Mark ([email-masked])

Cheers,

Dave
__________________________________________________________________________

   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.

===========================================================================
 
I am not sure what the whole story is, but look into the story about
ranitidine development by Sir James Black, who won the Nobel prize.
The drug is for ulcers.

Donald Doyle
UNC Chemistry

============================================================================

I will point out 3 other references:
Snyder, J. P. Med. Research Reviews, 11, 641-662, 1991
         John Wiley and Sons, Inc.
Navia, M. A. and Murcko, M. A. Current Opinion in Structural Biology
	2, 202-210, 1992
Kuntz, I. D,    Science 257, 1078-1082, 1992.

Kent Stewart
Abbott Laboratories

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	I am unaware of any commerically available drugs that have been 
design with the aid of computer modelling, however alot of work has been 
done on peptides and analodues of peptides as inhibitors of Angiotensin 
Converting Enzyme ACE. There have also been a number of studies of 
protease inhibitors, such as HIV Protease inhibitors using Sybil and the 
3D crystal structures from data bases such as Brookhaven. Dr. Robert 
Wiley and......? have written a review article on the subject. 

				Tim Volm
tvolm.blue.weeg.uiowa.edu

=============================================================================

One of the first from structure-based drug design will be Abbott's HIV protease
inhibitor. The NDA has not been filed yet. It was designed & synthesized almost
a decade ago, when the methods were much less robust.

Most of the earlier designed compounds have failed for one of the usual reasons.
This is true of our D1 dopaminergic agonists, first generation.

  @@@@@@@@@@@      Yvonne Martin, Senior Project Leader
             @     Computer Assisted Molecular Design Project
   @@@@@@@@  @     D-47E, AP10 2fl
  @          @     Abbott Laboratories
  @          @     100 Abbott Park Road
   @@@@@@@@@@      Abbott Park, IL 60064-3500
                   Phone: 708 937-5362 FAX: 708 937-2625

=============================================================================

Has anyone mentioned
the carbonic anhydrase inhibitor story?  Merck developed a CAI
drug for treatment of glaucoma using (among many other techniques!)
structure-based drug design.  This is the only example I know of 
that has actually been approved in the USA.  

============================================================================

	I hope this helps,

	Steven E. Schafer
	S.U.N.Y. Binghamton Chemistry Department
	http;//chemiris.chem.binghamton.edu:8080
	Binghamton, New York   USA