Abstract
The cyclic urea inhibitors of HIV-1 protease generally have two hydroxyl groups on the seven-membered ring. In this study, free energy perturbation and continuum electrostatic calculations were used to study the contributions of the two hydroxyl groups to the binding affinity and solubility of a cyclic urea inhibitor DMP323. The results indicated that the inhibitor with one hydroxyl group has better binding affinity and solubility than the inhibitor with two hydroxyl groups. Therefore, removal of one hydroxyl group from DMP323 may help to improve the properties of DMP323. This is also likely to be true for other cyclic urea inhibitors. The study also illustrated the difficulty in accurate modeling of the binding affinities of HIV-1 protease inhibitors, which involves many possible protonation states of the two catalytic aspartic acids in the active site of the enzyme.
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References
Debouck, C., AIDS Res. Human Retroviruses, 8 (1992) 153.
Katz, R.A. and Skalka, M., Ann. Rev. Biochem., 63 (1994) 133.
Weiss, R.A., Science, 260 (1993) 1273.
Johnston, M.I. and Hoth, D.E., Science, 260 (1993) 1286.
Suguna, K., Padlan, E.A., Smith, C.W., Carlson, W.D. and Davies, D.R., Proc. Natl. Acad. Sci., 84 (1987) 7009.
Wlodawer, A., Miller, M., Jaskolski, M., Sathyanarayana, B.K., Baldwin, E., Weber, I.T., Selk, L.M., Clawson, L., Schneider, L. and Kent, S.B.H., Science, 245 (1989) 616.
Wlodawer, A. and Vondrasek, J., Ann. Rev. Biophys. Biomol. Struct., 27 (1998) 249.
Thaisrivongs, S., Annu. Rep. Med. Chem., 29 (1994) 133.
Boehme, R.E., Borthwick, A.D. and Wyatt, P.G., Ann. Rep. Med. Chem., 30 (1995) 139.
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.
Lam, P.Y.S., Jadhav, P.K., Eyermann, C.J., Hodge, C.N., Ru, Y., Bacheler, L.T., Meek, J.L., Otto, M.J., Rayner, M.M., Wong, Y.N., Chang, C.H., Weber, P.C., Jackson, D.A., Sharpe, T.R. and Erickson-Viitanen, S., Science, 263 (1994) 380.
Sham, H.L., Zhao, C., Stewart, K.D., Betebenner, D.A., Lin, S., Park, C.H., Kong, X.P., Rosenbrook, J.W., Herrin, T., Madigan, D., Vasavanonda, S., Lyons, N., Molla, A., Saldivar, A., Marsh, K.C., McDonald, E., Wideburg, N.E., Denissen, J.F., Robins, T., Kempf, D.J., Plattner, J.J. and Norbeck, D.W., J. Med. Chem., 39 (1996) 392.
Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W. and Klein, M.L., J. Chem. Phys., 79 (1983) 926.
Pearlman, D.A., Case, D.A., Caldwell, J.W., Ross, W.S., T.E.C. III, Ferguson, D.M., Seibel, G.L., Singh, U.C., Weiner, P. and Kollman, P.A., AMBER, version 4.1, (1995) University of California at San Francisco.
Cornell, W.D., Cieplak, P., Bayly, C.I., Gould, I.R., Merz, K.M., Ferguson, D.M., Spellmeyer, D.C., Fox, T., Caldwell, J.W. and Kollman, P.A., J. Am. Chem. Soc., 117 (1995) 5179.
Bayly, C.I., Cieplak, P., Cornell, W.D. and Kollman, P.A., J. Phys. Chem., 97 (1993) 10269.
Frisch, M.J., Trucks, G.W., Schlegel, H.B., Gill, P.M.W., Johnson, B.G., Robb, M.A., Cheeseman, J.R., Keith, T., Petersson, G.A., Montegomery, J.A., Rahavachari, K., Al-Laham, M.A., Zakrzewski, V.G., Ortiz, J.V., Foresman, J.B., Peng, C.Y., Ayala, P.Y., Chen, W., Wong, M.W., Andres, J.L., Replogle, E.S., Gomperts, R., Martin, R.L., Fox, D.J., Binkley, J.S., Defrees, D.J., Baker, J., Stewart, J.P., Head-Gordon, M., Gonzalez, C. and Pople, J.A., Gaussian 94, Revision B.3, (1995) Gaussian Inc., Pittsburg, PA.
Ryckaert, J.P., Ciccotti, G. and Berendsen, H.J.C., J. Comput. Phys., 23 (1977) 327–341.
Miyamoto, S. and Kollman, P.A., J. Comput. Chem., 13 (1992) 952.
Berendsen, H.J.C., Postma, J.P.M., van Gunsteren, W.F., DiNola, A. and Haak, J.R., J. Chem. Phys., 81 (1984) 3684.
Åqvist, J., Medina, C. and Samuelsson, J.-E., Protein Eng., 7 (1994) 385–391.
Hansson, T. and Aqvist, J., Protein Eng., 8 (1995) 1137.
Chong, L.T., Y., D., Wang, L., Massova, I. and Kollman, P.A., Proc. Nat. Acad. Sci. USA, 96 (1999) 14330.
Jayaram, B., McConnell, K.J., Dixit, S.B. and Beveridge, D.L., J. Comput. Phys. 151 (1999) 333.
Kollman, P.A., Chem. Rev., 93 (1993) 2395.
Wang, L. and Hermans, J., J. Chem. Phys., 100 (1994) 9129.
Pearlman, D.A. and Kollman, P.A., J. Chem. Phys., 94 (1991) 4532.
Dang, LX, Merz, K.M., Jr. and Kollman, P.A., J. Am. Chem. Soc., 111 (1989) 8505.
Sun, Y.-C., Veenstra, D.L. and Kollman, P.A., Prot. Eng., 9 (1996) 273.
Mark, A.E. and van Gunsteren, W.F., J. Mol. Biol., 240 (1994) 167.
Ido, E., Han, H., Kezdy, F.J. and Tang, J., J. Biol. Chem., 266 (1991) 24359.
Sharp, K.A. and Honig, B., Ann. Rev. Biophys. Biophys. Chem., 19 (1990) 301.
Gilson, M.K., Sharp, K.A. and H., H.B., J. Phys. Chem., 9 (1988) 327.
Honig, B. and Nicholls, A., Science, 268 (1995) 1144.
Antosiewicz, J., McCammon, J.A. and Gilson, M.K., J. Mol. Biol., 238 (1994) 415.
Hine, J. and Mookerjee, P.K., J. Org. Chem., 40 (1975) 292.
Hyland, L.J., Tomaszek, J.T.A. and Meek, T.D., Biochemistry, 30 (1991) 8454.
Ferguson, D.M., Radmer, R.J. and Kollman, P.A., J. Med. Chem., 34 (1991) 2654.
Reddy, M.R., Viswanadhan, V.N. and Weinstein, J.N., Proc. Nat. Acad. Sci. USA, 88 (1991) 10287.
Tropsha, A. and Hermans, J., Protein Eng., 5 (1992) 29.
Rao, B.G., Tilton, R.F. and Singh, U.C., J. Am. Chem. Soc. 114 (1992) 4447.
Reddy, M.R., Varney, M.D., Kalish, V., Viswanadhan, V.N. and Appelt, K., J. Med. Chem., 37 (1994) 1145.
Chen, X.N. and Tropsha, A., J. Med. Chemi., 38 (1995) 42.
Rao, B.G. and Murcko, M.A., Protein Eng., 9 (1996) 767.
E., B.G.-M., Dwyer, J.J., Gittis, A.G., Lattman, E.E., Spencer, D.S. and Stites, W.E., Biophys. Chem., 64 (1997) 211.
Yamazaki, T., Nicholson, L.K., Torchia, D.A., Wingfield, P., Stahl, S.J., Kaufman, J.D., Eyermann, C.J., Hodge, C.N., Lam, P.Y.S., Ru, Y., Jadhav, P.K., Chang, C.H. and Weber, P.C., J. Am. Chem. Soc., 116 (1994) 10791.
Buono, G.S.D., Figueirido, F.E. and Levy, R.M., Proteins: Struct. Funct. Genet., 20 (1994) 85.
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Wang, L., Duan, Y., Stouten, P. et al. Does a diol cyclic urea inhibitor of HIV-1 protease bind tighter than its corresponding alcohol form? A study by free energy perturbation and continuum electrostatics calculations. J Comput Aided Mol Des 15, 145–156 (2001). https://doi.org/10.1023/A:1008156222963
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DOI: https://doi.org/10.1023/A:1008156222963