Abstract
Inhibition of dimerization to the active form of the HIV-1 aspartic proteinase (HIV-1 PR) may be a way to decrease the probability of escape mutations for this viral protein. The Multiple Copy Simultaneous Search (MCSS) methodology was used to generate functionality maps for the dimerization interface of HIV-1 PR. The positions of the MCSS minima of 19 organic fragments, once postprocessed to take into account solvation effects, are in good agreement with experimental data on peptides that bind to the interface. The MCSS minima combined with an approach for computational combinatorial ligand design yielded a set of modified HIV-1 PR C-terminal peptides that are similar to known nanomolar inhibitors of HIV-1 PR dimerization. A number of N-substituted 2,5-diketopiperazines are predicted to be potential dimerization inhibitors of HIV-1 PR.
Similar content being viewed by others
References
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) 4686.
Hoetelmans, R.M., Meenhorst, P.L., Mulder, J.W., Burger, D.M., Koks, C.H. and Beijnen, J.H., Pharm. World Sci., 19 (1997) 159.
Patick, A.K., Boritzki, T.J. and Bloom, L.A., Antimicrob. Agents Chemother., 41 (1997) 2159.
Sardana, V.V., Schlabach, A.J., Graham, P., Bush, B.L., Condra, J.H., Culberson, J.C., Gotlib, L., Graham, D.J., Kohl, N.E. and LaFemina, R.L., Biochemistry, 33 (1994) 2004.
Erickson, J.W., Nat. Struct. Biol., 2 (1995) 523.
Baldwin, E.T., Bhat, T.N., Liu, B., Pattabiraman, N. and Erickson, J.W., Nat. Struct. Biol., 2 (1995) 244.
Gulnik, S.V., Suvorov, L.I., Liu, B., Yu, B., Anderson, B., Mitsuya, H. and Erickson, J.W., Biochemistry, 34 (1995) 9282.
Ala, P.J., Huston, E.E., Klabe, R.M., MCabe, R.M., Duke, J.L., Rizzo, C.J., Korant, B.D., DeLoskey, R.J., Lam, P.Y., Hodge, C.N. and Chang, C.H., Biochemistry, 36 (1997) 1573.
Ermolieff, J., Lin, X. and Tang, J., Biochemistry, 36 (1997) 12364.
Rayner, M.M., Cordova, B. and Jackson, D.A., Virology, 236 (1997) 85.
Brodt, H.R., Kamps, B.S., Gute, P., Knupp, B., Staszewski, S. and Helm, E.B., AIDS, 11 (1997) 1731.
Zhang, Z.Y., Poorman, R.A., Maggiora, L., Heinrikson, R.L. and Kézdy, F.J., J. Biol. Chem., 266 (1991) 15591.
Schramm, H.J., Nakashima, H., Schramm, W., Wakayama, H. and Yamamoto, N., Biochem. Biophys. Res. Commun., 179 (1991) 847.
Schramm, H.J., Billich, A., Jaeger, E., Rücknagel, K.P., Arnold, G. and Schramm, W., Biochem. Biophys. Res. Commun., 194 (1993) 595.
Babé, L.M., Rosé, J. and Craik, C.S., Protein Sci., 1 (1992) 1244.
Schramm, H.J., Boetzel, J., Büttner, J., Fritsche, E., Göhring, W., Jaeger, E., König, S., Thumfart, O., Wenger, T., Nagel, N.E. and Schramm, W., Antiviral Res., 30 (1996) 155.
Zutshi, R., Franciskovich, J., Shultz, M., Schweitzer, B., Bishop, P., Wilson, M. and Chmielewski, J., J. Am. Chem. Soc., 119 (1997) 4841.
Bouras, A., Boggetto, N., Benatalah, Z., de Rosny, E., Sicsic, S. and Reboud-Ravaux, M., J. Med. Chem., 42 (1999) 957.
Miranker, A. and Karplus, M., Proteins Struct. Funct. Genet., 11 (1991) 29.
Venable, R.M., Brooks, B.R. and Carson, F.W., Proteins Struct. Funct. Genet., 15 (1993) 374.
Zheng, Q. and Kyle, D.J., Proteins Struct. Funct. Genet., 19 (1994) 324.
Zheng, Q. and Kyle, D.J., Biorg. Med. Chem., 4 (1996) 631.
Caflisch, A., J. Comput.-Aided Mol. Design, 10 (1996) 372.
Brooks, B.R., Bruccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S. and Karplus, M., J. Comput. Chem., 4 (1983) 187.
Lee, B. and Richards, F.M., J. Mol. Biol., 55 (1971) 379.
Padlan, E.A., Mol. Immun., 31 (1994) 169.
Loeb, D.D., Swanstrom, R., Everitt, L., Manchester, M., Stamper, S.E. and Hutchinson III, C.A., Nature, 340 (1989) 397.
Louis, J.M., Smith, C.A., Wondrak, E.M., Mora, P.T. and Oroszlan, S., Biochem. Biophys. Res. Commun., 164 (1989) 30.
Wlodawer, A., Miller, M., Jaskolski, M., Sathyanarayana, B.K., Baldwin, E., Weber, I.T., Selk, L., Clawson, L., Schneider, J. and Kent, S.B.H., Science, 245 (1989) 616.
Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, Jr., E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535.
Brünger, A. and Karplus, M., Proteins Struct. Funct. Genet., 4 (1988) 148.
Neria, E., Fischer, S. and Karplus, M., J. Chem. Phys., 105 (1996) 1902.
Caflisch, A., Miranker, A. and Karplus, M., J. Med. Chem., 36 (1993) 2142.
Miranker, A. and Karplus, M., Proteins Struct. Funct. Genet., 23 (1995) 472.
Caflisch, A. and Karplus, M., Persp. Drug Discov. Design, 3 (1995) 51.
Grootenhuis, P.D.J. and Karplus, M., J. Comput.-Aided Mol. Design, 10 (1996) 1.
Joseph-McCarthy, D., Hogle, J.M. and Karplus, M., Proteins Struct. Funct. Genet., 29 (1997) 32.
Gelin, B.R. and Karplus, M., Proc. Natl. Acad. Sci. USA, 72 (1975) 2002.
Caflisch, A. and Ehrhardt, C., In Veerapandian, P. (Ed.), Structure-Based Combinatorial Ligand Design. Structure-Based Drug Design, Marcel Dekker, Inc., New York, NY, 1997, pp. 541–558.
O'hea, E.K., Rutkowski, R. and Kim, P.S., Science, 243 (1989) 538.
O'hea, E.K., Klemm, J.D., Kim, P.S. and Alber, T., Science, 254 (1991) 539.
Still, W.C., Tempczyk, A., Hawley, R.C. and Hendrickson, T., J. Am. Chem. Soc., 112 (1990) 6127.
Sitkoff, D., Sharp, K.A. and Honig, B., J. Phys. Chem., 98 (1994) 1978.
Warwicker, J. and Watson, H.C., J. Mol. Biol., 157 (1982) 671.
Gilson, M.K. and Honig, B.H., Proteins Struct. Funct. Genet., 4 (1988) 7.
Bashford, D. and Karplus, M., Biochemistry, 29 (1990) 10219.
Davis, M.E., Madura, J.D., Luty, B.A. and McCammon, J.A., Comput. Phys. Commun., 62 (1991) 187.
Hermann, R.B., J. Phys. Chem., 76 (1972) 2754.
Chothia, C., Nature, 248 (1974) 338.
Honig, B. and Nicholls, A., Science, 268 (1995) 1144.
Ryckaert, J.P., Ciccotti, G. and Berendsen, H.J.C., J. Comput. Phys., 23 (1977) 327.
Klebe, G., Mietzner, T. and Weber, F., J. Comput.-Aided Mol. Design, 8 (1994) 751.
Grant, S.K., Deckman, I.C., Culp, J.S., Minnich, M.D., Brooks, I.S., Hensley, P., Debouck, C. and Meek, T.D., Biochemistry, 31 (1992) 9491.
Darke, P.L., Jordan, S.P., Hall, D.L., Zugay, J.A., Shafer, J.A. and Kuo, L.C., Biochemistry, 33 (1994) 98.
Reijers, M.H., Weverling, G.J., Jurriaans, S., Wit, F.W., Weigel, H.M., Ten-Kate, R.W., Mulder, J.W., Frissen, P.H., van Leeuwen, R., Reiss, P., Schuitemaker, H., de Wolf, F. and Lange, J.M., Lancet, 352 (1998) 185.
Kraulis, P., J. Appl. Crystallogr., 24 (1991) 946.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Caflisch, A., Schramm, H.J. & Karplus, M. Design of dimerization inhibitors of HIV-1 aspartic proteinase: A computer-based combinatorial approach. J Comput Aided Mol Des 14, 161–179 (2000). https://doi.org/10.1023/A:1008146201260
Issue Date:
DOI: https://doi.org/10.1023/A:1008146201260