QSAR and docking studies of inhibition activity of 5,6-dihydro 11-alkylbenzo[α]carbazole derivatives against estrogen receptor

In the present study, QSAR and docking studies were applied to understand the nature of 5,6-dihydro 11-alkylbenzo[α]carbazole derivatives and to investigate the interactions of homolog series with binding sites on selected a-chains of human estrogen receptors (hER). The best QSAR model was selected, having the correlation coeﬃcient r = 0.924, squared correlation coeﬃcient r2 = 0.854, standard deviation s = 0.357, and cross-validated squared correlation coeﬃcient Q2 = 0.755. The QSAR model indicated that the descriptors E-HOMO and heat of formation play an important role in human estrogen receptor inhibitor activities. A docking study was also utilized to visualize the interactions between the selected 2 compounds, 2 and 3, as estrogen inhibitors and human estrogen receptor. The results of the present study may be useful in the designing of more potent 5,6-dihydro 11-alkylbenzo[α]carbazole derivatives as estrogen receptor inhibitor agents.

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1. von Angerer, E.; Prekajac, J.; Strohmeier, J. J. Med. Chem. 1984, 27, 1439-1447.
2. von Angerer, E.; Prekajac, J. J. Med. Chem. 1986, 29, 380-386.
3. Katritzky, W. J. Heterocyc. Chem. 1988, 25, 671-675.
4. Pappa, H.; Segall, A.; Pizzorno, M. T.; Radice, M.; Amoroso, A.; Gutkind, G. Il Farmaco 1994, 49, 333-336.
5. Segall, A.; Pappa, H.; Casaubon, R.; Martin, G.; Bergoc, R.; Pizzorno, M. T. Eur. J. Med. Chem. 1995, 30, 165-169.
6. Macchia, M.; Manera, C.; Nencetti, S.; Rossello, A.; Brocalli, G.; Limonta, D. Il Farmaco 1996, 51, 75-78.
7. Segall, A.; Pappa, H.; Pizzorno, M. T.; Radice, M.; Amoroso, A.; Gutkind, G. Il Farmaco 1996, 51, 513-516.
8. Amoroso, A.; Radice, M.; Segall, A.; Rodero, L.; Hochenfellner, F.; Pizzorno, M. T.; Moretton, J.; Garrido, D.; Gutkind, G. Pharmazie 2000, 55, 151-152.
9. Segall, A.; Pizzorno, M. T. Pharmazie 2000, 55, 766- 767.
10. Martin, G.; Cocca, C.; Rivera, E.; Cricco, G.; Segall, A.; Pappa, H.; Casaubon, R.; Caro, R.; Pizzorno, M. T.; Bergoc, R. J. Exp. Ther. Oncol. 2002, 2, 77-84.
11. LePecq,J.B.;Dat-Xoung,N.;Gosse,C.;Paoletti,C. Proc. Natl. Acad. Sci. 1974, 71, 5078.
12. Pelaprat, D.; Oberlin, R.; Le Guen, I.; Roques, B. P.; LePecq, J. B. J. Med. Chem. 1980, 23, 1330.
13. (a) Martin, G.; Cocca, C.; Rivera, E.; Cricco, G.; Caro, R.; Segall, A.; Pappa, H.; Casaubon, R.; Pizzorno, M. T.; Bergoc,R.M. J. Exp.Ther. Oncol. 2002, 2, 77-84. (b) Dantas, S. O.; Lavarda, F. C.; Galvao, D. S.; Laks, B. J. Mol. Struc. Theochem. 1992, 253, 319. (c) Dantas, S. O.; Galvao, D. S. J. Mol. Struc. Theochem. 1992, 43, 257.
14. Poliakoﬀ, N.; Albonico, S. M.; Alvarez, M.; Pecca, J. G.; Vernengo, M. J. J. Med. Chem. 1973, 16, 1411.
15. Pahsa, F. A.; Srivastava, H. K.; Singh, P. P. Int. J. Quantum Chem. 2005, 104, 87-100.
16. Taskin, T.; Sevin, F. J. Mol. Struct.: THEOCHEM 2007, 803, 61-66.
17. Angerer, E.; Prekajac, J. J. Med. Chem. 1986, 3, 29.
18. BILIN, Donnersbergstrasse 9, D–67256 Weisenheim am Sand, Germany, 2005.
19. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J. Am. Chem. Soc. 1985, 107, 3902.
20. Stewart, J. J. P. J. Comp. Chem. 1989, 10, 209.
21. (a) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and Molecules, Oxford University Press, New York, 1989. (b) Kohn, W.; Becke, A. D.; Parr, R. G. J. Phys. Chem. 1996, 100, 12974.
22. Demo ICM-Pro version 3.4.8, Molsoft LLC, 3366 North Torrey Pines Court, Suite 300, La Jolla, CA 92037, USA.
23. Fernandez-Recio, J.; Totrov, M.; Skorodumov, C.; Abagyan, R. Proteins: Structure, Function, and Bioinformatics 2005, 58, 134-143.
24.Frisch,M.J.;Trucks,G.W.;Schlegel,H.B.;Scuseria,G.E.;Robb,M.A.;Cheeseman,J.R.;Montgomery,J. A. Jr; Vreven, T.; Kudin, K. N.; Burant, J. C; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci B.; Cossi M.; Scalmani G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C. J.; Ochterski, W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Cliﬀord, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian03, Revision B.01 Gaussian Inc., Pittsburgh, PA, 2003.
25. Chattaraj, P. K.; Nath, S.; Maiti, B. Reactivity Descriptors. In: Tollenaere, J.; Bultinck, P.; Winter H.D.; Lange- naeker, W., Editors; Computational Medicinal Chemistry and Drug Discovery, Marcel Dekker, New York, 2003, pp. 295-322, Chapter 11.
26. Parr, R. G.; Szentpaly, L. V.; Liu, S. J. Am. Chem. Soc. 1999, 121, 1922.
27. Maynard, A. T.; Huang, M.; Rice, W. G.; Covell, D. G. Proc. Natl. Acad. Sci. USA 95, 1998, 11578-11583
28. Srikanth, K.; Debnath, B.; Jha, T. Bioorg. Med. Chem. 2002, 10, 1841-1854.