HIV protease: Structure-based design


Close examination of the X-ray crystallographic structures of complexes of prototypical HIV protease inhibitors drawn from diverse structural classes and bound to either synthetic or recombinant HIV protease reveals a remarkable degree of conservation vis-à-vis the protein's homodimeric backbone geometry and key features of its inhibitor binding site. Subtle concerted movements of the amino acid side chains lining this cavity and making contact with inhibitors are evident in exquisite detail in the most highly resolved structures. They are responsible for the enzyme's selectivity. As noted in the preceding perspective on X-ray crystallographic studies, HIV protease is rapidly becoming one of the most well-studied proteins.

As a modeler one is encouraged to use the available structural data to predict the binding modes of other classes of HIV protease inhibitors for which X-ray data are unavailable and also as templates to guide the design of further novel inhibitors, which hopefully have some advantages over existing structures. The improvements sought typically involve structural simplification, metabolic stability, or most of all, increased in vivo potency and oral bioavailability. While the structural outcome may or may not bear resemblance to any one of the original reference inhibitor structures, we refer to this process as one ofstructure-based design to emphasize its dependence on critical analyses of the properties and behavior of these experimental datasets.

Computational methodologies are available to analyze and compare these datasets in some depth, and to display and manipulate them interactively, in various complementary visualization formats, as a preliminary to undertaking any structurally directed synthetic initiatives. Likewise, efficient molecular-mechanics software tools are on hand to explore the conformational changes around the active site, which are needed to build in or to dock models of new inhibitor structures; either prospectively, for evaluation as potential synthetic targets, or retrospectively, to help rationalize the SAR of a known series or lead in the context of a more realistic active site-bound model.

To date these design techniques and strategies have been applied mainly to the optimization of established peptidomimetic leads and to rationalize the binding modes of new peptidomimetic inhibitor classes. However, examples exist of applications to the binding modes of nonpeptidic inhibitors and of limited attempts at de novo structure-based design.

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  1. 1

    Navia, M.A. and Murcko, M.A., Curr. Opin. Struct. Biol., 2 (1992) 202.

    Google Scholar 

  2. 2

    Erickson, J.W. and Fesik, S.W., Annu. Rep. Med. Chem., 27 (1992) 271.

    Google Scholar 

  3. 3

    Norbeck, D.W. and Kempf, D.J., Annu. Rep. Med. Chem., 26 (1991) 141.

    Google Scholar 

  4. 4

    Martin, J.A., Antiviral Res., 17 (1992) 265.

    Google Scholar 

  5. 5

    Huff, J.R., J. Med. Chem., 34 (1991) 2305.

    Google Scholar 

  6. 6

    Miller, M., Schneider, J., Sathyanarayana, B.K., Toth, M.V., Marshall, G.R., Clawson, L., Kent, S.B. and Wlodawer, A., Science, 246 (1989) 1149.

    Google Scholar 

  7. 7

    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., Science, 245 (1989) 616.

    Google Scholar 

  8. 8

    Swain, A.L., Miller, M., Green, J., Rich, D.H., Schneider, J., Kent, S.B. and Wlodawer, A., Proc. Natl. Acad. Sci. USA, 87 (1990) 8805.

    Google Scholar 

  9. 9

    Bone, R., Vacca, J.P., Anderson, P.S. and Holloway, M.K., J. Am. Chem. Soc., 113 (1991) 9382.

    Google Scholar 

  10. 10 a.

    Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyor, E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535.

    Google Scholar 

  11. 10 b.

    Abola, E.E., Bernstein, F.C., Bryant, S.H., Koetzle, T.F. and Weng, J., In Allen, F.H., Bergerhoff, G. and Sievers, R. (Eds.) Crystallographic Databases — Information Content, Software Systems, Scientific Applications, Data-Commission of the International Union of Crystallography, Bonn/Cambridge/Chester, 1987, pp. 107–132.

    Google Scholar 

  12. 11

    Schechter, I. and Berger, A., Biochem. Biophys. Res. Commun., 27 (1967) 157.

    Google Scholar 

  13. 12

    Harte Jr., W.E., Swaminathan, S., Mansuri, M.M., Martin, J.C., Rosenberg, I.E. and Beveridge, D.L., Proc. Natl. Acad. Sci. USA, 87 (1990) 8864.

    Google Scholar 

  14. 13

    Goodford, P.J., J. Med. Chem., 28 (1985) 849.

    Google Scholar 

  15. 14

    Lee, B. and Richards, F.M., J. Mol. Biol., 55 (1971) 379.

    Google Scholar 

  16. 15

    Bohacek, R.S. and McMartin, C., J. Med. Chem., 35 (1992) 1671.

    Google Scholar 

  17. 16

    SYBYL, Version 6.0, TRIPOS Associates, Inc., 1699 S. Hanley Rd., Suite 303, St. Louis, MO 63144-2913, 1992.

  18. 17

    Ho, C.M. and Marshall, G.R., J. Comput.-Aided Mol. Design, 4 (1990) 337.

    Google Scholar 

  19. 18

    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., Martin, 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 

  20. 19

    Rich, D.H., Sun, C.Q., Vara-Prasad, J.V., Pathiasseril, A., Toth, M.V., Marshall, G.R., Clare, M., Mueller, R.A. and Houseman, K., J. Med. Chem., 34 (1991) 1222.

    Google Scholar 

  21. 20

    Weiner, S.J., Kollman, P.A., Case, D.A., Singh, U.C., Ghio, C., Alagona, G., Profeta, S. and Weiner, P., J. Am. Chem. Soc., 106 (1984) 765.

    Google Scholar 

  22. 21

    Vedani, A. and Huhta, D.W., J. Am. Chem. Soc., 112 (1990) 4759.

    Google Scholar 

  23. 22 a.

    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., Adv. Exp. Med. Biol., 306 (1991) 455.

    Google Scholar 

  24. 22 b.

    Krohn, A., Redshaw, S., Ritchie, J.C., Graves, B.J. and Hatada, M.H., J. Med. Chem., 34 (1991) 3340.

    Google Scholar 

  25. 23

    Getman, D.P., DeCrescenzo, G.A., Heintz, R.M., Reed, K.L., Talley, J.J., Bryant, M.L., Clare, M., Houseman, K.A., Marr, J.J., Mueller, R.A., Vazquez, M.L., Shieh, H.-S., Stallings, W.C. and Stegeman, R.A., J. Med. Chem., 36 (1993) 288.

    Google Scholar 

  26. 24

    Bash, P.A., Singh, U.C., Langridge, R. and Kollman, P.A., Science, 236 (1987) 564.

    Google Scholar 

  27. 25

    Rao, B.G., Tilton, R.F. and Singh, U.C., J. Am. Chem. Soc., 114 (1992) 4447.

    Google Scholar 

  28. 26

    Ferguson, D.M., Radmer, R.J. and Kollman, P.A., J. Med. Chem., 34 (1991) 2654.

    Google Scholar 

  29. 27

    Young, S.D., Payne, L.S., Thompson, W.J., Gaffin, N., Lyle, T.A., Britcher, S.F., Graham, S.L., Schultz, T.H., Deana, A.A., Darke, P.L., Zugay, J., Schlief, W.A., Quintero, J.C., Emini, E.A., Anderson, P.S. and Huff, J.R., J. Med. Chem., 35 (1992) 1702.

    Google Scholar 

  30. 28

    Thompson, W.J., Fitzgerald, P.M., Holloway, M.K., Emini, E.A., Darke, P.L., McKeever, B.M., Schlief, 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 

  31. 29 a.

    Tucker, T.J., Lumma Jr., W.C., Payne, L.S., Wai, J.M., De Solms, S.J., Giuliani, E.A., Darke, P.L., Heimbach, J.C., Zugay, J.A., Schleif, W.A., Quintero, J.C., Emini, E.A., Huff, J.R. and Anderson, P.S., J. Med. Chem., 35 (1992) 2526.

    Google Scholar 

  32. 29 b.

    Vacca, J.P., Dorsey, B.D., Guare, J.P., Holloway, M.K. and Hungate, R.W., World PatentWO9309096 (1993).

  33. 30

    Martin, J.A. and Thomas, G.J., European Patent EP-512343-A2 (1992).

  34. 31

    Hammond, M. and Kaldor, S.W., European Patent EP-526009-A1 (1993).

  35. 32

    Thaisrivongs, 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 

  36. 33

    Moon, J.B. and Howe, W.J., Proteins, 11 (1991) 314.

    Google Scholar 

  37. 34

    Humber, D.C., Cammack, N., Coates, J.A.V., Cobley, K.N., Orr, D.C., Storer, R., Weingarten, G.G. and Weir, M.P., J. Med. Chem., 35 (1992) 3080.

    Google Scholar 

  38. 35

    Kitchin, J., Holmes, D.S., Humber, D., Storer, R., Dolan, S.C., Hann, M.M., McMeekin, P., Murray-Rust, P. and Weingarten, G.G., World Patent WO9301174-A1 (1993).

  39. 36

    Bures, M.G., Hutchins, C.W., Maus, M., Kohlbrenner, W., Kadam, S. and Erickson, J.W., Tetrahedron Comput. Meth., 3 (1990) 673.

    Google Scholar 

  40. 37

    Van Drie, J.H., Weininger, D. and Martin, Y.C., J. Comput.-Aided Mol. Design, 3 (1989) 225.

    Google Scholar 

  41. 38 a.

    Lam, P.Y.-S., Eyermann, C.J., Jadhav, P.K., Hodge, C.N., Ru, Y., DeLucca, G.V., Batcheler, L.T., Meek, J.L., Otto, M.J., Rayner, M.M., Wong, N.Y., Chang, C.-H., Weber, P.C., Jackson, D.A., Sharpe, T.R. and Erickson-Viitanen, S., IXth International Conference on AIDS, Berlin (1993) Poster A25 O585.

  42. 38 b.

    Lam, P.Y.-S., Eyermann, C.J., Hodge, C.N., Jadhav, P.K. and DeLucca, G.V., World Patent WO9307128-A1 (1993).

  43. 39

    Chenera, B., DesJarlais, R.L. and Dreyer, G., World Patent WO9221647-A1 (1992).

  44. 40

    Lewis, R.A., Roe, D.C., Huang, C., Ferrin, T.E., Langridge, R. and Kuntz, I.D., J. Mol. Graphics, 10 (1992) 66.

    Google Scholar 

  45. 41

    DesJarlais, R.L., Seibel, G.L., Kuntz, I.D., Furth, P.S., Alvarez, J.C., Ortiz-de-Montellano, P.R., Decamp, D.L., Babe, L.M. and Craik, C.S., Proc. Natl. Acad. Sci. USA, 87 (1990) 6644.

    Google Scholar 

  46. 42

    Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 61.

    Google Scholar 

  47. 43

    Miranker, A. and Karplus, M., Proteins, 11 (1991) 29.

    Google Scholar 

  48. 44

    Wiley, R.A. and Rich, D.H., Med. Res. Rev., 13 (1993) 327.

    Google Scholar 

  49. 45

    Lingham, R.B., Hsu, A., Silverman, K.C., Bills, G.F., Dombrowski, A., Goldman, M.E., Darke, P.L., Huang, L., Koch, G. and Ondeyka, J.G., J. Antibiot., 45 (1992) 686.

    Google Scholar 

  50. 46

    Greenlee, W.J., Med. Res. Rev., 10 (1990) 173.

    Google Scholar 

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Clare, M. HIV protease: Structure-based design. Perspectives in Drug Discovery and Design 1, 49–68 (1993).

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Key words

  • Enzyme
  • Inhibitor
  • Design
  • HIV-1
  • Protease