Successful Examples of Rational Drug Design
- From: wcg()at()ussu.ciba.com (Wayne C. Guida)
- Subject: Successful Examples of Rational Drug Design
- Date: Thu, 17 Jun 1993 17:29:03 -0400
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()wucmd.wustl.edu) writes:
>mike whitbeck (whitbeck()at()maxey.unr.edu) 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
demonstrated.
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
role.
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
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Wayne C. Guida
Pharmaceuticals Division
Ciba
556 Morris Ave.
Summit, New Jersey 07901
Phone: 908-277-7954
Internet:
wcg()at()ussu.ciba.com
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