Summary: success stories in molecular design (long)

 Here is a summary of the responses.  Thank you very much to all who replied.
 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: inoue.,at,
      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
      --David Saari                              saarid.,at,
      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                        saarid.,at,.pt.Cyanamid.COM
 Hi Dave--
 Glad to have a chance to make your aquaintance!  This is sitting
 on my hard drive, so I don't even have to try myself, or suggest
 you try Jan's "search" thing...
 reissner.,at,       Ph: (310)825-5151;  Fax: (310)206-3566
 Dep't Chem and Biochem, MC 156905, UCLA, 405 Hilgard Ave., LA 90024- 1569
 Home: 972 Hilgard Ave., Apt. 302, Los Angeles, CA 90024 Ph: (310)824-1732
 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                        D.Winkler.,at,
 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
   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
   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:
     There are numerous examples of "designed" compounds that have
 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
 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
 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
 Alex Vlodower and John Erickson have a recent review on the HIV protease
 Yvonne Martin
 Abbott Laboratories
 There was also a recent ACS Satellite Symposium on the topic.
 >From MARTIN.,at,.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
         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
 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
 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:  marty.,at,
 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
 Chem, and the one on explanatory power is to be printed in Drug Design and
 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
 * "_initial_idea_ for a nonpetide inhibitor that includes a structural
 mimic"  (exact quote) - this suggests that someone in the group came with
 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  =
    tudor.,at,  =
 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 (markm.,at,
    Dr. David A. Winkler                        Voice: 61-3-542-2244
    Principal Research Scientist                Fax:   61-3-543-8160
    CSIRO Division of Chemicals and Polymers
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