From wcg "-at-" ussu.Ciba.Com Thu Jun 17 13:29:03 1993 Date: Thu, 17 Jun 1993 17:29:03 -0400 From: wcg#* at *#ussu.ciba.com (Wayne C. Guida) Message-Id: <9306172129.AA10805&$at$&pharma.ussu.Ciba.Com> To: CHEMISTRY "-at-" ccl.net Subject: 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 +)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 ========================================================================= Wayne C. Guida Pharmaceuticals Division Ciba 556 Morris Ave. Summit, New Jersey 07901 Phone: 908-277-7954 Internet: wcg \\at// ussu.ciba.com =========================================================================