Successful Examples of Rational Drug Design

 Dear Netters,
     There has been some conversation recently concerning examples in which
 computational methods have been used successfully for rational drug design.
 Mark Smythe (mls()at() writes:
 >mike whitbeck (whitbeck()at() writes:
 >...(deleted parts of message)
 >I recall awhile back there was some traffic about 'has comp. chem. methods
 >ever developed a new drug ?' I no longer recall the consensus of that
 >conversation (or was it on the drug discovery list out of oz?).
 >If anyone recalls a concrete example where the calculations made the
 >difference tell us about it.
 >...(deleted parts of message)
 ...(deleted parts of message)
      I would like to point out that there are several examples of
 structure-based drug design in which computational methods in conjunction
 with protein crystallographic methods have PROVEN to be successful in
 the design of enzyme inhibitors that have therapeutic utility.
      The most recent example is the one Mark Smythe referred to in
 his recent email, and which appeared in Nature, 363, 418-423 (1993). This
 work involves the rational design of sialidase inhibitors for treatment
 of influenza. Note that the therapeutic value in man has yet to be
      In their excellent chapter in Annual Reports in Medicinal Chemistry
 (Chapter 29 - "Macromolecular X-ray Crystallography and NMR as Tools for
 Structure-based Drug Design", Volume 27, 1992, Academic Press),
 John Erickson and Stephen Fesik cite several additional earlier
 examples (though the emphasis is on X-ray and NMR).  In their
 article they describe the iterative design of thymidylate synthase (TS)
 inhibitors by the group at Agouron Pharmaceuticals as well as our work
 (a collaborative effort between Ciba and Biocryst Pharmaceuticals) on the
 iterative design of inhibitors of Purine Nucleoside Phosphorylase (PNP). In
 both cases computer assisted molecular modeling definitely played a critical
      I believe that Agouron has at least one TS inhibitor in clinical
 trials and Biocryst has reported successful Phase I/II clinical trials for
 BCX-34, a PNP inhibitor that was discovered as a result of the
 structure-based drug design effort mentioned above.
      For references to our work on PNP inhibitors, see: Ealick, et. al.,
 Proc. Natl. Acad. Sci. USA, 88, 11540 (1991) for the "Readers Digest"
 version and Montgomery, et. al., J. Med. Chem., 36, 55-69 (1993) for paper
 #1 of a series of J. Med. Chem. papers that are either in press, submitted,
 or in preparation.
 -Wayne C. Guida
 Wayne C. Guida
 Pharmaceuticals Division
 556 Morris Ave.
 Summit, New Jersey 07901
 Phone: 908-277-7954