Abstract
A panel of 92 catechol-O-methyltransferase (COMT) inhibitors was used to examine the molecular interactions affecting their biological activity. COMT inhibitors are used as therapeutic agents in the treatment of Parkinson's disease, but there are limitations in the currently marketed compounds due to adverse side effects. This study combined molecular docking methods with three-dimensional structure-activity relationships (3D QSAR) to analyse possible interactions between COMT and its inhibitors, and to incite the design of new inhibitors. Comparative molecular field analysis (CoMFA) and GRID/GOLPE models were made by using bioactive conformations from docking experiments, which yielded q2 values of 0.594 and 0.636, respectively. The docking results, the COMT X-ray structure, and the 3D QSAR models are in agreement with each other. The models suggest that an interaction between the inhibitor's catechol oxygens and the Mg2+ ion in the COMT active site is important. Both hydrogen bonding with Lys144, Asn170 and Glu199, and hydrophobic contacts with Trp38, Pro174 and Leu198 influence inhibitor binding. Docking suggests that a large R1 substituent of the catechol ring can form hydrophobic contacts with side chains of Val173, Leu198, Met201 and Val203 on the COMT surface. Our models propose that increasing steric volume of e.g. the diethylamine tail of entacapone is favourable for COMT inhibitory activity.
Similar content being viewed by others
References
Männistö, P.T. and Kaakkola, S., Pharmacol. Rev., 51 (1999) 593.
Axelrod, J. and Tomchick, R., J. Biol. Chem., 233 (1958) 702.
Guldberg, H.C. and Marsden, C.A., Pharmacol. Rev., 27 (1975) 135.
Bonifati, V. and Meco, G., Pharmacol. Ther., 81 (1999) 1.
Gordin, A., Kaakkola, S. and Teräväinen, H., Adv. Neurol., 91 (2003) 237.
Guttman, M., Leger, G., Reches, A., Evans, A., Kuwabara, H., Cedarbaum, J.M. and Gjedde, A., Mov. Disord., 8 (1993) 298.
Najib, J., Clin. Ther., 23 (2001) 802.
De Santi, C., Giulianotti, P.C., Pietrabissa, A., Mosca, F. and Pacifici, G.M., Eur. J. Clin. Pharmacol., 54 (1998) 215.
Zurcher, G., Colzi, A. and Da Prada, M.J., Neural. Transm. Suppl., 32 (1990) 375.
Micek, S.T. and Ernst, M.E., Am. J. Health Syst. Pharm., 56 (1999) 2195.
Olanow, C.W., Arch. Neurol., 57 (2000) 263.
Taskinen, J., Vidgren, J., Ovaska, M., Bäckström, R., Pippuri, A. and Nissinen, E., Quant. Struct.-Act. Relat., 8 (1989) 210.
Lotta, T., Taskinen, J., Bäckström, R. and Nissinen, E., J. Comput.-Aided Mol. Des., 6 (1992) 253.
Cramer III, R.D., Patterson, D.E. and Bunce, J.D., J. Am. Chem. Soc., 110 (1988) 5959.
Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, I.N., Shindyalov, P.E. and Bourne, P.E., Nucleic Acids Res., 28 (2000) 235.
Vidgren, J., Svensson, L.A. and Liljas, A., Nature, 368 (1994) 354.
Buolamwini, J.K. and Assefa, H., J. Med. Chem., 45 (2002) 841.
Sippl, W., J. Comput.-Aided Mol. Des., 14 (2000) 559.
Liu, H., Huang, X., Shen, J., Luo, X., Li, M., Xiong, B., Chen, G., Yang, Y., Jiang, H. and Chen, K., J. Med. Chem., 45 (2002) 4816.
Böhm, H.J., J. Comput.-Aided Mol. Des., 8 (1994) 243.
Goodford, P.J., J. Med. Chem., 28 (1985) 849.
Baroni, M., Costantino, G., Cruciani, G., Riganelli, D., Valigi, R. and Clementi, S., Quant. Struct.-Act. Relat., 12 (1993) 9.
Sybyl 6.8, Tripos Inc., St. Louis, MO.
Sadowski, J. and Gasteiger, J., Chem. Rev., 93 (1993) 2567.
Sadowski, J., Gasteiger, J. and Klebe, G., J. Chem. Inf. Comput. Sci., 34 (1994) 1000.
Clark, M., Cramer III, R.D. and Van Opdenbosch, N., J. Comput. Chem., 10 (1989) 982.
Rarey, M., Kramer, B., Lengauer, T. and Klebe, G., J. Mol. Biol., 261 (1996) 470.
Gasteiger, J. and Marsili, M., Tetrahedron, 36 (1980) 3219.
Purcell, W.P. and Singer, J.A., J. Chem. Eng. Data 12 (1967) 235.
Stewart, J.J., J. Comput.-Aided Mol. Des., 4 (1990) 1.
Besler, B.H., Merz, K.M. and Kollman, P.A., J. Comput. Chem., 11 (1990) 431.
Cramer III, R.D., Bunce, J.D. and Patterson, D.E., Quant. Struct.-Act. Relat., 7 (1988) 18.
Oprea, T.I. and Garcia, A.E., J. Comput.-Aided Mol. Des., 10 (1996) 186.
Pastor, M., Cruciani, G. and Clementi, S., J. Med. Chem., 40 (1997) 1455.
Clark, R.D., Strizhev, A., Leonard, J.M., Blake, J.F. and Matthew, J.B., J. Mol. Graph. Model., 20 (2002) 281.
Wallace, A.C., Laskowski, R.A. and Thornton, J.M., Protein Eng., 8 (1995) 127.
Lehtonen, J. V., Rantanen, V.-V., Still, D.-J., Ekholm, J., Björklund, D., Iftikhar, Z., Huhtala, M., Jussila, A., Jaakkola, J., Pentikäinen, O.T., Nyrönen, T.A., S.T., Gyllenberg, M. and Johnson, M.S., BODIL: a molecular modeling environment for structure-function analysis and drug discovery, unpublished, http://www.abo.fi/fak/mnf/bkf/ research/johnson/bodil.html.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tervo, A.J., Nyrönen, T.H., Rönkkö, T. et al. A structure-activity relationship study of catechol-O-methyltransferase inhibitors combining molecular docking and 3D QSAR methods. J Comput Aided Mol Des 17, 797–810 (2003). https://doi.org/10.1023/B:JCAM.0000021831.47952.a7
Issue Date:
DOI: https://doi.org/10.1023/B:JCAM.0000021831.47952.a7