Perspectives in Drug Discovery and Design

, Volume 1, Issue 1, pp 23–48 | Cite as

Crystal structures of HIV-1 protease-inhibitor complexes

  • Krzysztof Appelt


HIV PR is one of the most popular targets for the development of drugs for treatment of AIDS and in the last few years, a significant effort has been directed towards its structure elucidation in both liganded and unliganded form. In this review, 25 available crystal structures of HIV PR complexes with inhibitors are described. Binding of peptidic inhibitors to the HIV PR active site are analyzed in view of the formation of potential hydrogen bonds and filling of hydrophobic space. A potential impact of the accumulated crystallographic effort on the development of computational methods for structure-based drug design is briefly addressed.

Key words

HIV protease Protease inhibitors X-ray structure Active site-inhibitor interaction 


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  1. 1.
    Mitsuya, H., Yarchoan, R. and Broder, S., Science, 249 (1990) 1533.Google Scholar
  2. 2.
    Tomasselli, A.G., Howe, J.W., Sawyer, T.K., Wlodawer, A. and Heinrikson, R.L., Chimica Oggi, 9 (1991) 6.Google Scholar
  3. 3.
    Kohl, N.E., Emini, E.A., Schleif, W.A., Davis, L.J., Heimbach, J.C., Dixon, R.A.F., Scolnick, E.M. and Sigal, I.S., Proc. Natl. Acad. Sci. USA, 85 (1988) 4186.Google Scholar
  4. 4.
    McQuade, T.K., Tomasselli, A.G., Liu, L., Karacostas, V., Moss, B., Sawyer, T.K., Heinrikson, R.L. and Tarpley, W.G., Science, 247 (1990) 454.Google Scholar
  5. 5.
    Toh, H., Ono, M., Saigo, K. and Miyata, T., Nature, 315 (1985) 691.Google Scholar
  6. 6.
    Krausslich, H.G., Ingraham, R.H., Skoog, M.T., Wimmer, E., Pallai, P.V. and Carter, C.A., Proc. Natl. Acad. Sci. USA, 86 (1989) 807.Google Scholar
  7. 7.
    Heimbach, J.C., Garsky, V.M., Michelson, S.R., Dixon, R.A.F., Sigal, I.S. and Darke, P.L., Biochem. Biophys. Res. Commun., 164 (1989) 955.Google Scholar
  8. 8.
    Schneider, J. and Kent, S.B.H., Cell, 54 (1988) 363.Google Scholar
  9. 9.
    Wlodawer, A. and Erickson, J.W., Annu. Rev. Biochem., 62 (1993) 543.Google Scholar
  10. 10.
    Miller, M., Schneider, J., Sathyanarayana, B.K., Toth, M.V., Marshall, G.R., Clawson, L., Selk, L., Kent, S.B.H. and Wlodawer, A., Science, 246 (1989) 1149.Google Scholar
  11. 11.
    Swain, A.L., Miller, M., Green, J., Rich, D.H., Schneider, J., Kent, S.B.H. and Wlodawer, A., Proc. Natl. Acad. Sci. USA, 87 (1990) 8805.Google Scholar
  12. 12.
    Jaskolski, M., Tomasselli, A.G., Sawyer, T.K., Staples, R.L., Heinrikson, R.L., Schneider, J., Kent, S.B.H. and Wlodawer, A., Biochemistry, 30 (1991) 1600.Google Scholar
  13. 13.
    Erickson, J.W., Neidhardt, D.J., VanDrie, J., Kempf, D.J., Wang, X.C., Norbeck, D.W., Plattner, J.J., Rittenhouse, J.W., Turon, M., Wideburg, N., Kohlbrenner, W.E., Simmer, R., Helfrich, R., Paul, D.A. and Knigge, M., Science, 249 (1990) 527.Google Scholar
  14. 14.
    Fitzgerald, P.M.D., McKeever, B.M., VanMiddleworth, J.F., Springer, J.P., Heimbach, J.C., Leu, C.-T., Herber, W.K., Dixon, R.A.F. and Darke, P.L., J. Biol. Chem., 265 (1990) 14209.Google Scholar
  15. 15.
    Graves, B.J., Hatada, M.H., Miller, J.K., Graves, M.C., Roy, S., Cook, C.M., Krohn, A., Martin, J.A. and Roberts, N.A., In Dunn, B. (Ed.) Structure and Function of the Aspartic Proteinases, Plenum Press, New York, 1992, pp. 455–460.Google Scholar
  16. 16.
    Bone, R., Vacca, J.P., Anderson, P.S. and Holloway, M.K., J. Am. Chem. Soc., 113 (1991) 9382.Google Scholar
  17. 17.
    Krohn, A., Redshaw, S., Ritchie, J.C. and Hatada, M.H., J. Med. Chem., 34 (1991) 3340.Google Scholar
  18. 18.
    Dreyer, G.B., Lambert, D.M., Meek, T.D., Carr, T.J., Tomaszek, T.A., Fernandez, A.V., Bartus, H., Cacciavillani, E., Hassel, A.M., Minnich, M., Petteway Jr., S.R., Metcalf, B.W. and Lewis, M., Biochemistry, 31 (1992) 6646.Google Scholar
  19. 19.
    Thanki, N., Rao, J.K.M., Foundling, S.I., Howe, W.J., Moon, J.B., Tomasselli, A.G., Heinrikson, R.L., Thaisrivongs, S. and Wlodawer, A., Protein Sci., 1 (1992) 1061.Google Scholar
  20. 20.
    Thompson, W.J., Fitzgerald, P.M.D., Holloway, M.K., Emini, E.A., Darke, P.L., Keever, B.M., Schleif, W.A., Quintero, J.C., Zugay, J.A., Tucker, T.J., Schwering, J.E., Homnick, C.F., Nunberg, J., Springer, J.P. and Huff, J.R., J. Med. Chem., 35 (1992) 1685.Google Scholar
  21. 21.
    Humber, D.C., Cobley, K.N., Evans, D.N., Storer, R., Weingarten, G.G., Hann, M.M., Mistry, A., Wonacott, A., Cammack, N. and Orr, D.C., VIIIth International Conference on AIDS, Amsterdam, 1992, POA 2280.Google Scholar
  22. 22.
    Dreyer, B.G., Boehm, J.C., Chenera, B., DesJarlais, R.L., Hassel, A.M., Meek, T.D., Tomaszek, T.A. and Lewis, M., Biochemistry, 32 (1993) 937.Google Scholar
  23. 23.
    Pearl, L.N. and Taylor, W.R., Nature, 329 (1987) 351.Google Scholar
  24. 24.
    Miller, M., Jaskolski, M., Rao, J.K.M., Leis, J. and Wlodawer, A., Nature, 337 (1989) 576.Google Scholar
  25. 25.
    Navia, M.A., Fitzgerald, P.M.D., McKeever, B.M., Leu, C.-T., Heimbach, J.C., Herber, W.K., Sigal, I.S., Darke, P.L. and Springer, J.P., Nature, 337 (1989) 615.Google Scholar
  26. 26.
    Lapatto, R., Blundell, T., Hemmings, A., Overington, J., Wilderspin, A., Wood, S., Merson, J.R., Whittle, P.J., Danley, D.E., Geoghegan, K.F., Havrylik, S.J., Lee, S.E., Scheld, K.G. and Hobart, P.M., Nature, 342 (1989) 299.Google Scholar
  27. 27.
    Wlodawer, A., Miller, M., Jaskolski, M., Sathyanarayana, B.K., Baldwin, E., Weber, I.T., Selk, L.M., Clawson, L., Schneider, J. and Kent, S.B.H., Science, 245 (1989) 616.Google Scholar
  28. 28.
    Tang, J., James, M.N.G., Hsu, I.N., Jenkins, J.A. and Blundell, T., Nature, 271 (1978) 618.Google Scholar
  29. 29.
    Meek, T.D., Lambert, B.W., Metcalf, B.W., Petteway Jr., S.R. and Dreyer, G.B., In De Clercq, E. (Ed.) Design of Anti-AIDS Drugs, Elsevier, Amsterdam, 1990, p. 225.Google Scholar
  30. 30.
    Blundell, T., Jenkins, J.A., Pearl, L.H., Sewell, T. and Pedersen, V., In Kostka, V. (Ed.) Aspartic Proteinases and Their Inhibitors, De Gruyter, Berlin, 1985, pp. 151–161.Google Scholar
  31. 31.
    James, M.N.G. and Sielecki, A., J. Mol. Biol., 163 (1983) 299.Google Scholar
  32. 32.
    Schechter, I. and Berger, A., Biochem. Biophys. Res. Commun., 27 (1967) 157.Google Scholar
  33. 33.
    Wlodawer, A., Nachman, J., Gilliland, G.L., Gallagher, W. and Woodward, C., J. Mol. Biol., 198 (1987) 469.Google Scholar
  34. 34.
    Lewis, P.N., Momany, F.A. and Scheraga, H.A., Proc. Natl. Acad. Sci. USA, 68, (1971) 2293.Google Scholar
  35. 35.
    Swain, A.L., Gustchina, A. and Wlodawer, A., In Dunn, B. (Ed.) Structure and Function of the Aspartic Proteinase: Genetics, Structure and Mechanism, Plenum Press, New York, NY, 1992, pp. 433–441.Google Scholar
  36. 36.
    Thaisrivongs, S., Pals, D.T., Kroll, L.T., Turner, S.R. and Han, F.-S., J. Med. Chem., 30 (1987) 976.Google Scholar
  37. 37.
    Taisrivongs, S., Tomasselli, A.G., Moon, J.B., Hui, J., McQuade, T.J., Turner, S.R., Strohbach, J.W., Howe, W.J., Tarpley, W.G. and Heinrikson, R.L., J. Med. Chem., 34 (1991) 2344.Google Scholar
  38. 38.
    Ryono, D.E., Free, C.A., Neubeck, R., Samaniego, S.G., Godfrey, J.D. and Petrillo Jr., E.W. In Deber, C.M., Hruby, V.J. and Kopple, K.D. (Eds.) Peptides, Structure and Function, Proceedings of the Ninth American Peptide Symposium, Pierce Chemical and Co, 1985, pp. 739–748.Google Scholar
  39. 39.
    Dann, J.G., Stammers, D.K., Harris, C.J., Arrowsmith, R.J., Davies, D.E., Hardy, G.W. and Morton, J.A., Biochem. Biophys. Res. Commun., 134 (1986) 71.Google Scholar
  40. 40.
    Rich, D.H., Green, J., Toth, M.V., Marshall, G.R. and Kent, S.B.H., J. Med. Chem., 33 (1990) 1285.Google Scholar
  41. 41.
    Roberts, N.A., Martin, J.A., Kinchington, D., Broadhurst, A.V., Craig, J.C., Duncan, I.B., Galpin, S.A., Handa, B.K., Kay, J., Krohn, A., Lambert, R.W., Merrett, J.H., Mills, J.S., Parkes, K.E.B., Redshaw, S., Ritchie, A.J., Taylor, D.L., Thomas, G.J. and Machin, P.J., Science, 248 (1990) 358.Google Scholar
  42. 42.
    Rich, D.H., Sun, Ch.-Q., Vara Prasad, J.V.N., Pathiasseril, A., Toth, M.V., Marshall, G.R., Clare, M., Mueller, R.A. and Hauseman, K., J. Med. Chem., 34 (1991) 1222.Google Scholar
  43. 43.
    Huff, J.R., J. Med. Chem., 34 (1991) 2305.Google Scholar
  44. 44.
    VanDrie, J.H., Weininger, D. and Martin, Y.C., J. Comput.-Aided Mol. Design, 3 (1989) 225.Google Scholar
  45. 45.
    Kuntz, I.D., Blanley, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.Google Scholar
  46. 46.
    Van Gunsteren, W.F. and Berendsen, H.J.C., Angew. Chem. Int. Ed. Eng., 29 (1990) 992.Google Scholar
  47. 47.
    Rami Reddy, M., Bacquet, R.J., Zichi, D., Matthews, D.A., Welsh, K.M., Jones, T.R. and Freer, S., J. Am. Chem. Soc., 114 (1992) 10117.Google Scholar
  48. 48.
    Rami Reddy, M., Viswanadhan, V.N. and Weinstein, J.N., Proc. Natl. Acad. Sci. USA, 88 (1991) 10287.Google Scholar
  49. 49.
    Rami Reddy, M., Varney, M., Kalish, V., Viswanadhan, V.N. and Appelt, K., submitted to Science.Google Scholar
  50. 50.
    Fitzgerald, P,M.D., McKeever, B.M., VanMiddlesworth, J.F. and Springer, J.P., In Kumar, A. (Ed.) Advances in Molecular Biology and Targeted Treatment for AIDS, Plenum Press, New York, 1991, pp. 245–249.Google Scholar
  51. 51.
    Rutenber, E., Fauman, E.B., Keenan, R.J., Fong, S., Furth, P.S., Oritz de Montellano, P.R., Meng, E., Kuntz, I.D., DeCamp, D.L., Salto, R., Rose, J.R., Craik, C.S. and Stroud, R.M., J. Biol. Chem., 1993, in press.Google Scholar
  52. 52.
    DesJarlais, R.L., Seibel, G.L., Kuntz, I.D., Furth, P.S., Alvarez, J.C., Ortiz de Montello, J.C., DeCamp, D.L., Babe, L.M. and Craik, C.S., Proc. Natl. Acad. Sci. USA, 87 (1990) 6644.Google Scholar

Copyright information

© ESCOM Science Publishers B.V 1993

Authors and Affiliations

  • Krzysztof Appelt
    • 1
  1. 1.Agouron Pharmaceuticals Inc.San DiegoUSA

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