Abstract
Three-dimensional quantitative structure-activity relationship (3D QSAR) methods were applied on a series of inhibitors of HIV-1 integrase with respect to their inhibition of 3′-processing and 3′-end joining steps in vitro.The training set consisted of 27 compounds belonging to the class of thiazolothiazepines. The predictive ability of each model was evaluated using test set I consisting of four thiazolothiazepines and test set II comprised of seven compounds belonging to an entirely different structural class of coumarins. Maximum Common Substructure (MCS) based method was used to align the molecules and this was compared with other known methods of alignment. Two methods of 3D QSAR: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were analyzed in terms of their predictive abilities. CoMSIA produced significantly better results for all correlations. The results indicate a strong correlation between the inhibitory activity of these compounds and the steric and electrostatic fields around them. CoMSIA models with considerable internal as well as external predictive ability were obtained. A poor correlation obtained with hydrophobic field indicates that the binding of thiazolothiazepines to HIV-1 integrase is mainly enthalpic in nature. Further the most active compound of the series was docked into the active site using the crystal structure of integrase. The binding site was formed by the amino acid residues 64-67, 116, 148, 151-152, 155-156, and 159. The comparison of coefficient contour maps with the steric and electrostatic properties of the receptor shows high level of compatibility.
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Hariprasad, V., Talele, T.T., Kulkarni, V.M., Pharm. Pharmacol. Commun., 4 (1998) 365.
De Clercq, E., J. Med. Chem., 38 (1995) 2491.
Richman, D.D., Nature, 410 (2001) 995.
Sakai, H., Kawamura, M., Sakuragi, J., Sakuragi, S., Shibata, R., Ishimoto, A., Ono, H., Ueda, S., Adachi, A., J. Virol., 67 (1993), 1169.
Taddeo, B., Haseltine, W. A., Farnet, C.M., J. Virol., 68 (1994) 8401.
Engelman, A., Englund, G., Orenstein, J.M., Martin, M.A., Craigie, R., J. Virol., 69 (1995) 2729.
Goff, S.P., Annu. Rev. Genet., 26 (1992) 527.
Vink, C., Plasterk, R.H.A., Trends Genet., 9 (1993) 433.
Craigie, R., Trends Genet., 8 (1992) 187.
LaFemina, R.L., Schneider, C.L., Robibins, H.L., Callahan, P.L., LeGrow, K., Roth, E., Schleif, W.A., Emini, E.A., J. Virol., 66 (1992) 7414.
Craigie, R., Trends Genet., 8 (1992) 187.
Stanwell, C., Ye, B., Yuspa, S.H., Burke, T.R., Jr., Biochem. Pharmacol., 52 (1996) 475.
Neamati, N., Hong, H., Owen, J.M., Sunder, S., Winslow, H.E., Christensen, J.L., Zhao, H., Burke, J.T.R., Milne, G.W.A., Pommier, Y., J. Med. Chem., 41 (1998) 3202.
Neamati, N., Hong, H., Mazumder, A., Wang, S., Sunder, S., Nicklaus, M. C., Milne, G.W., Proksa, B., Pommier, Y., J. Med. Chem., 40 (1997) 942.
Pommier, Y., Pilon, A., Bajaj, K., Mazumder, A., Neamati, N., Antiviral Chem. Chemother., 8 (1997) 483.
Neamati, N., Sunder, S., Pommier, Y., Drug Discovery Today, 2 (1997) 487.
Nicklaus, M.C., Neamati, N., Hong, H., Mazumder, A., Sunder, S., Chen, J., Milne, G.W., Pommier, Y., J. Med. Chem., 40 (1997) 920.
Neamati, N., Mazumder, A., Zhao, H., Sunder, S., Burke, T.R., Jr., Schultz, R.J., Pommier, Y., Antimicrob. Agents Chemother., 41 (1997) 385.
Neamati, N., Mazumder, A., Sunder, S., Owen, J.M., Schultz, R.J., Pommier, Y., Antiviral Chem. Chemother., 8 (1997) 485.
Neamati, N., Turpin, J.A., Winslow, H.E., Christensen, J.L., Williamson, K., Orr, A., Rice, W.G., Pommier, Y., Garofalo, A., Brizzi, A., Campiani, G., Fiorini, I., Nacci, V.J., Med. Chem., 42 (1999) 3334.
Cramer, R.D., III, Patterson, D.E., Bunce, J.D., J. Am. Chem. Soc., 110 (1988) 5959.
Kulkarni, S.S., Kulkarni, V.M., J. Med. Chem., 42 (1999) 373.
Gokhale, V.M., Kulkarni, V.M., J. Med. Chem., 42 (1999) 5348.
Cho, S.J., Tropsha, A., J. Med. Chem., 38 (1995) 1060.
Klebe, G., Abraham, U., Mietzner, T., J. Med. Chem., 37 (1994) 4130.
Klebe, G., Perspect Drug Discovery Des., 12 (1998) 87.
Bohm, M., Sturzebecher, J., Klebe, G., J. Med. Chem., 42 (1999) 458.
Zhao, H., Neamati, N., Hong, H., Mazumder, A., Wang, S., Sunder, S., Milne, G.W.A., Pommier, Y., Burke, T.R., Jr., J. Med. Chem., 40 (1997) 242.
Makhija, M.T., Kulkarni, V.M., J. Chem. Inf. Comput. Sci., (2001) (appeared online in October 5th issue).
SYBYL Molecular Modeling System, Version 6.6; Tripos, Inc., St. Louis, MO 63144-2913.
Clark, M., Cramer, R.D., III, Van Opdenbosh, N.J., Comput. Chem., 10 (1989) 982.
MOPAC 6.0 is available from Quantum Chemistry Program Exchange, Indiana University.
Stewart, J.J.P., J. Comput.-Aided Mol. Des., 4 (1990) 1.
Kearsley, S.K., Smith, G.M., Tetrahedron Comput. Methodol., 3 (1990) 615.
Wold, S., Albano, C., Dunn, W.J., III, Edlund, U., Esbensen, K., Geladi, P., Hellberg, S., Johansson, E., Lindberg, W., Sjostrom, M., Multivariate Data Analysis in Chemistry. In CHEMOMETRICS: Mathematics and Statistics in Chemistry; Kowalski, B., Ed.; Reidel: Dordrecht, The Netherlands, 1984.
Waller, C.L., Oprea, T.L., Giolitti, A., Marshall, G.R., J. Med. Chem., 36 (1993) 4152.
Cramer, R.D., III, Bunce, J.D., Patterson, D.E., Quant. Struct. Act. Relat., 7 (1988) 18.
Cerius2 3.5 is available from Molecular Simulations Inc., Scranton Road, San Diego, CA.
Raghavan, K., Buolamwini, J.K., Fesen, M.R., Pommier, Y., Kohn, K.W., Weinstein, J., J. Med. Chem., 38 (1995) 890.
SYBYL ‘Ligand-Based Design Manual’ version 6.6; Tripos, Inc., St. Louis, MO.
Ouali, M., Laboulais, C., Leh, H., Gill, D., Desmaele, D., Mekouar, K., Zouhiri, F., Angelo, J., Auclair, C., Mouscadet, J.F., Bret, M.L., J. Med. Chem., 43 (2000) 1949.
Ma, C.J., Dougherty, D.A., Chem. Rev., 97 (1997) 1303.
Goldgur, Y., Craigie, R., Cohen, H.G., Fujiwara, T., Yoshinaga, T., Fujishita, T., Sugimoto, H., Endo, T., Murai, H., Davies, R.D., Proc. Natl. Acad. Sci. USA, 96 (1999) 13040.
Levit, M., Lifson, S., J. Mol. Biol., 46 (1969) 269.
Gokhale, V.M., Kulkarni, V.M., J. Comput.-Aided Mol. Des., 14 (2000) 495.
Orozco, M., Laughton, C.A., Herzyk, P., Neidle, S., J. Biomol. Struct. Dyn., 8 (1990) 359.
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Makhija, M.T., Kulkarni, V.M. 3D-QSAR and molecular modeling of HIV-1 integrase inhibitors. J Comput Aided Mol Des 16, 181–200 (2002). https://doi.org/10.1023/A:1020137802155
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DOI: https://doi.org/10.1023/A:1020137802155