Abstract
Our interest lies in the rational design and synthesis of type-III mimetics of protein and polypeptide structure and function. Our approach involves interactive design of conformationally defined molecular scaffolds that project certain functional groups in a way that mimics the projection of important binding residues as determined in the parent structure. These design principles are discussed and applied to the structurally defined polypeptide, ω-conotoxin GVIA, which blocks voltage-gated, neuronal N-type calcium channels. These ion channels represent therapeutic targets for the development of new analgesics that can treat chronic pain. It is shown how a discontinuous, 3-residue pharmacophore of GVIA can be mimicked by different molecular scaffolds. It is illustrated how such 1st generation leads must necessarily be weak and that optimisability must therefore be built-in during the design process.
Similar content being viewed by others
References
Ripka, A.S. and Rich, D.H., Curr. Opin. Chem. Biol., 2 (1998) 441.
Kasher, R., Oren, D., Barda, Y. and Gilon C., J. Mol. Biol., 292 (1999) 421 (and references therein).
Tilley, J.W., Chen, L., Fry, D.C., Emerson, S.D., Powers, G.D., Biondi, D., Varnell, T., Trilles, R., Guthrie, R., Mennona, F., Kaplan, G., LeMahieu, R.A., Carson, M., Han, R.-J., Liu, C.-M., Palermo, R. and Ju, G., J. Am. Chem. Soc., 119 (1997) 7589.
Sarabu, R., Cooper, J.P., Cook, C.M. Gillespie, P., Perrotta, A.V. and Olson, G.L., Drug Des. Discov., 15 (1998) 191.
Menzler, S., Bikker, J.A., Suman-Chauhan, N. and Horwell, D.C., Bioorg. Med. Chem. Lett., 10 (2000) 345.
Perrier, V., Wallace, A.C., Kaneko, K., Safar, J., Prusiner, S.B. and Cohen, F.E., Proc. Natl. Acad. Sci. USA, 97 (2000) 6073.
Lauri, G. and Bartlett, P.A., J. Comput. Aid. Mol. Des., 8 (1994) 51.
Yang, W., He, H. and Drueckhammer, D.G., Angew. Chem. Int. Ed., 40 (2001) 1714.
Norton, R.S. and Pallaghy, P.K., Toxicon, 36 (1998) 1573.
Lew, M.J., Flinn, J.P., Pallaghy, P.K., Murphy, R., Whorlow, S.L., Wright, C.E., Norton, R.S. and Angus, J.A., J. Biol. Chem., 272 (1997) 12014.
Flinn, J.P., Pallaghy, P.K., Lew, M.J., Murphy, R., Angus, J.A. and Norton, R.S., Eur. J. Biochem., 262 (1999) 447.
Norton, R.S., Pallaghy, P.K., Baell, J.B., Wright, C.E., Lew, M.J. and Angus, J.A., Drug Develop. Res., 46 (1999) 206.
Halgren, T.A., J. Comput. Chem., 20 (1999) 720.
Sprague, J.M. and Land, A.H., in Elderfield, R.C. (ed.), Heterocyclic Compounds, Volume 5, Wiley, New York, 1957, pp. 484-722.
Williams, D.H. and Westwell, M.S., Chem. Soc. Rev., 27 (1998) 57.
Pallaghy, P.K. and Norton, R.S., J. Pept. Res., 53 (1999) 343.
Goldenberg, D.P., Koehn, R.E., Gilbert, D.E. and Wagner, G., Protein Sci., 10 (2001) 538.
Vaughan, C.K., Buckle, A.M. and Fersht, A.R., J. Mol. Biol., 286 (1999) 1487.
Bogan, A.A. and Thorn, K.S., J. Mol. Biol., 280 (1998) 1.
Clackson, T., Ultsch, M.H., Wells, J.A. and de Vos, A.M., J. Mol. Biol., 277 (1998) 1.
Shapiro, R., Ruiz-Gutierrez, M. and Chen, C.-Z., J. Mol. Biol., 302 (2000) 497.
Kuehlmann, U.C., Pommer, A.J., Moore, G.R., James, R. and Kleanthous, C., J. Mol. Biol., 301 (2000) 1163.
Reinemer, P., Sebald, W. and Duschl, A., Angew. Chem. Int. Ed., 39 (2000) 2834.
Clackson, T. and Wells, J., Science, 267 (1995) 383.
For a useful review on small molecule inhibitors of proteinprotein interactions, see Cochran, A., Chem. Biol., 7 (2000) R85.
Plummer, M.S., Holland, D.R., Shahripour, A., Lunney, E.A., Fergus, J.H., Marks, J.S., McConnell, P., Mueller, W.T. and Sawyer T.K., J. Med. Chem., 40 (1997) 3719.
Andrade-Gordon P., Maryanoff, B.E., Derian, C.K., Zhang, H.-C., Addo, M.F., Darrow, A.L., Eckardt, A.J., Hoekstra, W.J., McComsey, D.F., Oksenberg, D., Reynolds, E.E., Santulli, R., Scarborough, R.M., Smith, C.E. and White, K.B., Proc. Natl. Acad. Sci. USA, 96 (1999) 12257.
Liuzzi, M., Deziel, R., Moss, N., Beaulieu, P., Bonneau, A.-M., Bousquet, C., Chafouleas, J.G., Garneau, M., Jaramillo, J., Krogsrud, R.L., Lagace, L., McCollum, R.S., Nawoot, S. and Guindon, Y., Nature, 372 (1994) 695.
Qian, Y., Vogt, A., Vasudevan, A., Sebti, S.M. and Hamilton, A.D., Bioorg. Med. Chem., 6 (1998) 293.
Stanfield, R.L. and Wilson, I.A., Curr. Opin. Struct. Biol., 5 (1995) 103.
Sulyok, G.A.G., Gibson, C., Goodman, S.L., Hoelzemann, G., Wiesner, M. and Kessler, H., J. Med. Chem., 44 (2001) 1938.
Orner, B.P., Ernst, J.T. and Hamilton, A.D., J. Am. Chem. Soc., 123 (2001) 5382.
Scanlon, M.J., Fairlie, D.P., Craik, D.J., Englebretsen, D.R. and West, M.L., Biochem., 34 (1995) 8242.
Petros, A.M., Nettesheim, D.G., Wang, Y., Olejniczak, E.T., Meadows, R.P., Mack, J., Swift, K., Matayoshi, E.D., Zhang, H., Thompson, C.B. and Fesik, S.W., Protein Sci., 9 (2000) 2528.
Sheldrick, G.M., 'SHELXS-97'. Program for crystal structure solution, University of Goettingen, Germany (1997).
Sheldrick, G.M., 'SHELXL-97'. Program for crystal structure refinement, University of Goettingen, Germany (1997).
Kaduk, C., Wenschuh, H., Beyermann, M., Forner, K., Carpino, L. and Bienert, M., Lett. Pept. Sci., 2 (1995) 285.
Feichtinger, K., Sings, H.L., Baker, T.J., Matthews, K. and Goodman, M., J. Org. Chem., 63 (1998) 8432.
Kiso, Y., Ukawa, K., Nakamura, S., Ito, K. and Akita, T., Chem. Pharm. Bull., 28 (1980) 673.
Miel, H. and Rault, S., Tetrahedron Lett., 38 (1997) 7865. No mention is made of problematic tin salts in workup (if product fails to crystallise), which we found best dealt with by use of aqueous sodium potassium tartrate.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Baell, J.B., Forsyth, S.A., Gable, R.W. et al. Design and synthesis of type-III mimetics of ω-conotoxin GVIA. J Comput Aided Mol Des 15, 1119–1136 (2001). https://doi.org/10.1023/A:1015930031890
Issue Date:
DOI: https://doi.org/10.1023/A:1015930031890