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The following HTML text is provided to enhance online readability. Many aspects of typography translate only awkwardly to HTML. Please use the page image as the authoritative form to ensure accuracy. While a natural product discovered by such a screen will itself only rarely become a drug (its potency, selectivity, bioavailability, and/or stability may be inadequate), it may suggest a type of structure that would interact with the target, serving as a point of departure for a medicinal chemistry effort—i.e., it may be a "lead." It is still beyond our capability to design, routinely, such lead structures, based simply upon knowledge of the structure of our target. However, if a drug discovery target contains regions of structure homologous to that in other proteins, structures known to interact with those proteins may prove useful as leads for a medicinal chemistry effort. The specificity of a lead for a target may be optimized by directing structural variation to specificity-determining sites and away from those sites required for interaction with conserved features of the targeted protein structure. Strategies that facilitate recognition and exploration of sites at which variation is most likely to generate a novel function increase the efficiency with which useful molecules can be created. I am grateful to Thomas Eisner and Jerrold Meinwald for organizing this thought-provoking Colloquium; to Gerald Bills, Ralph Hirschmann, Joel Huff, Chris Sander, Catherine Strader, Gary Stoecker, and especially, Jerrold Meinwald for their very helpful comments on earlier versions of this manuscript; and to Marianne Belcaro for assistance with its preparation. REFERENCES1. Merck & Co. (1993) Annual Report (Merck & Co., Rahway, NJ). 2. Alberts, A. W., Chen, J., Kuron, G., Hunt, V., Huff, J., et al. (1980) Proc. Natl. Acad. Sci. USA 77, 3957-3961. 3. Kahan, J. S., Kahan, F. M., Goegelman, R., Currie, S. A., Jackson, M., Stapley, E. O., Miller, T. W., Miller, A. K., Hendlin, D., Mochales, S., Hernandez, S., Woodruff, H. B. & Bimbaum, J. (1978) J. Antibiot. 32, 1-12. 4. Ferreira, S. H. (1965) Br. J. Pharmacol. 24, 163-169. 5. Ondetti, M. A., Rubin, B. & Cushman, D. W. (1977) Science 196, 441-444. 6. Patchett, A. A., Harris, E., Tristam, E. W., Wyvratt, M., Wu, M. T., et al. (1980) Nature (London) 288, 280-283. 7. Imperato-McCinley, J., Guerrero, L., Gautier, T., & Petersen, R. (1974) Science 186, 1213-1215. 8. Kohl, N. E., Emini, E. A., Schleif, W. A., Davis, L. J., Heimbach, J. C., Dixon, R. A. F., Scolnick, E. M. & Sigal, I. S. (1988) Proc. Natl. Acad. Sci. USA 85, 4686-4690. 9. Huff, J. R. (1991) J. Med. Chem. 34, 2305-2314. 10. Wiley, R. A. & Rich, D. H. (1993) Med. Res. Rev. 13, 327-384. 11. Lingham, R. B., Hsu, A., Silverman, K.C., Bills, G. F., Dombrowski, A., Goldman, M. E., Darke, P. L., Huang, L., Koch, G., Ondeyka J. G. & Goetz, M. A. (1992) J. Antibiot. 45, 686-691. 12. Kashman, Y., Gustafson, K. R., Fuller, R. W., Cardellina, J. H., McMahon, J. B.,
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