Molecular docking and QSAR study on imidazole derivatives as $14alpha$ -demethylase inhibitors

Molecular docking and QSAR study on imidazole derivatives as $14alpha$ -demethylase inhibitors

14 $alpha$-Demethylase (CYP51) inhibitors have been widely used in the treatment of fungal infections. In this study, a series of imidazole derivatives with CYP51 inhibitory activity were subjected to a molecular docking study followed by quantitative structure{activity relationship (QSAR) analyses in search of the ideal physicochemical characteristics of potential CYP51 inhibitors. Desired imidazoles were built using the HyperChem program, and conformational studies were performed through a semiempirical method followed by the PM3 method. Docking study was performed using the AutoDock program on all of the compounds. Di erent QSAR descriptors were calculated using DRAGON, AutoDock, and HyperChem. Multilinear regression was used as a chemometric tool for QSAR modeling. The docking study indicated that all of compounds 1-43 interact with the 14$alpha$ -demethylase, and azole{heme coordination and$Pi-Pi$and $Pi$ -cation interactions are involved in drug{ receptor interaction. In the$Pi-Pi$and $Pi$ -cation interactions, the aryl moieties interact with Phe 255 and Arg 96, and the role of the phenoxy group is more important than that of the phenyl group. The developed QSAR model indicated the importance of atomic van der Waals volumes and atomic Sanderson electronegativities. The sums of the R6u, RDF030v, Mor25v, GATs5e, and R5e+ were identi ed as the most signi cant descriptors. The developed QSAR model was statistically signi cant according to the validation parameters.

___

  • 1. Rostom, S. A.; Ashour, H. M.; El Razik, H. A.; El Fattah Ael, F.; El-Din, N. N. Bioorg. Med. Chem. 2009, 17, 2410{2422.
  • 2. Minari, A.; Husni, R.; Avery, R. K.; Longworth, D. L.; DeCamp, M.; Bertin, M.; Schilz, R.; Smedira, N.; Haug, M. T.; Mehta, A.; Gordon, S. M. Transpl. Infect. Dis. 2002, 4, 195{200.
  • 3. Edmond, M. B.; Wallace, S. E.; McClish, D. K.; Pfaller, M. A.; Jones, R. N.; Wenzel, R. P. Clin. Infect. Dis. 1999, 29, 239{244.
  • 4. Steenbergen, J. N.; Casadevall, A. J. Clin. Microbiol. 2000, 38, 1974{1976.
  • 5. Latge, J. P. Clin. Microbiol. Rev. 1999, 12, 310{350.
  • 6. De Luca, L. Curr. Med. Chem. 2006, 13, 1{23.
  • 7. Zhu, J.; Lu, J.; Zhou, Y.; Li, Y.; Cheng, J.; Zheng, C. Bioorg. Med. Chem. Lett. 2006, 16, 5285{5289.
  • 8. Roberts, T. R.; Hutson, D. Metabolic Pathways of Agrochemicals. Part 2: Insecticides and Fungicides, Royal Society of Chemistry, Cambridge, 1999.
  • 9. Sheehan, D. J.; Hitchcock, C. A.; Sibley, C. M. Clin. Microbiol. Rev. 1999, 12, 40{79.
  • 10. Vanden Bossche, H.; Koymans, L. Mycoses 1998, 41, 32{38.
  • 11. Georgopapadakou, N. H.; Walsh, T. J. Antimicrob. Agents Chemother. 1996, 40, 279{291.
  • 12. Lupetti, A.; Danesi, R.; Campa, M.; Tacca, M. D.; Kelly, S. Trends Mol. Med. 2002, 8, 76{81.
  • 13. Weinberg, E. D. In Burger's Medicinal Chemistry and Drug Discovery; Abraham, D. J., Ed.; John Wiley & Sons, New York, 1996.
  • 14. Slama, J. T.; Hancock, J. L.; Rho, T.; Sambucetti, L.; Bachmann, K. A. Biochem. Pharmacol. 1998, 55, 1881{1892.
  • 15. Wul , H.; Miller, M. J.; Hansel, W.; Grissmer, S.; Cahalan, M. D.; Chandy, K. G. Proc. Nat. Acad. Sci. USA 2000, 97, 8151{8156.
  • 16. Sakaeda, T.; Iwaki, K.; Kakumoto, M.; Nishikawa, M.; Niwa, T.; Jin, J.; Nakamura, T.; Nishiguchi, K.; Okamura, N.; Okumura, K. J. Pharm. Pharmacol. 2005, 57, 759{764.
  • 17. Ho man, H. L.; Ernst, E. J.; Klepser, M. E. Expert Opin. Invest. Drugs 2000, 9, 593-605.
  • 18. Casalinuovo, I. A.; Di Francesco, P.; Garaci, E. Eur. Rev. Med. Pharmacol. Sci. 2004, 8, 69.
  • 19. Silvestri, R.; Artico, M.; La Regina, G.; Di Pasquali, A.; De Martino, G.; D'Auria, F. D.; Nencion, L.; Palarmara, A. T. J. Med. Chem. 2004, 47, 3924{3926.
  • 20. La Regina, G.; D'Auria, F. D.; Ta , A.; Piscitelli, F.; Olla, S.; Caporuscio, F.; Nencioni, L.; Cirilli, R.; La Torre, F.; De Melo, N. R.; Kelly, S. L.; Lamb, D. C.; Artico, M.; Botta, M.; Palamara, A. T.; Silestri, R. J. Med. Chem. 2008, 51, 3841{3855.
  • 21. Roy, P. P.; Roy, K. J. Pharm. Pharmacol. 2010, 62, 1717{1728.
  • 22. Dai, Y.; Wang, Q.; Zhang, X.; Jia, S.; Zheng, H.; Feng, D. Eur. J. Med. Chem. 2010, 45, 5612{5620.
  • 23. Saz-Urra, L.; Perez, M. A. C.; Helguera, A. M.; Froeyen, M. Eur. J .Med. Chem. 2011, 46, 2736{2747.
  • 24. Davood, A.; Nematollahi, A.; Iman, M.; Sha ee, A. Med. Chem. Res. 2010, 19, 58-70.
  • 25. Davood, A.; Iman, M. Med. Chem. Res. 2011, 20, 955{961.
  • 26. Nematollahi, A; Davood, A. Int. J. Chem.Tech Res. 2010, 2 1808{1815.
  • 27. Iman, M.; Davood, A.; Nematollahi, A.; Dehpoor, A. R.; Sha ee, A. Arch. Pharm. Res. 2011, 34, 1417{1426.
  • 28. Masanda, V. H; Mahajana, D. T; Patila, K. N; Padoleb, N; Haddac, T. B; Alafeefyd, A. A. J. Comput. Method. Mol. Design 2011, 1, 49{56.
  • 29. Pana, X.; Tana, N.; Zenga, G.; Hana, H.; Huanga, H Bioorg. Med. Chem. 2006, 14, 2771{2778.
  • 30. Wang, Q.; Mach, R. H.; Reichert, D. E. J. Chem. Inf. Model. 2009, 49 1963{1973.
  • 31. Cherkasov, A.; Ban, F.; Li, Y.; Fallahi, M J. Med. Chem. 2006, 49, 7466{7478.
  • 32. Morris, G. M.; Goodsell, D. S.; Pique, M. E.; Lindstrom, W. L.; Huey, R.; Forli, S.; Hart, W. E.; Halliday, S.; Belew, R.; Olson, A. J. AutoDock 4.2 with AutoDockTools. http://autodock.scripps.edu/faqs-help/manual/autodock-4- 2-user-guide/AutoDock4.2 UserGuide.pdf, 2009.
  • 33. Podust, L. M.; Poulos, T. L.; Waterman, M. R. Proc. Natl. Acad. Sci. 2001, 98, 3068.
  • 34. Todeschini, R. Milano Chemometrics and QSAR Group, http://michem.disat.unimib.it/, e-dragon (http://www.vcclab.org/ lab/edragon), 2008.
Turkish Journal of Chemistry-Cover
  • ISSN: 1300-0527
  • Yayın Aralığı: Yılda 6 Sayı
  • Yayıncı: TÜBİTAK
Sayıdaki Diğer Makaleler

Synthesis, characterization, and swelling behaviors of a pH-responsive CMC-g-poly(AA-co-AMPS) superabsorbent hydrogel

Yizhe WANG, Xiaoning SHI, Wenbo WANG, Aiqin WANG

Electrochemical properties of 1,3-disubstituted methyl methoxy phenyl-5-phenylformazans and comparison with spectral properties

Habibe TEZCAN, Güler EKMEKCİ, M. Levent AKSU

Molecular docking and QSAR study on imidazole derivatives as $14alpha$ -demethylase inhibitors

Maryam IMAN, Asghar DAVOOD

Molecular docking and QSAR study on imidazole derivatives as 14 /alpha -demethylase inhibitors

Asghar DAVOOD, Maryam IMAN

Mechanochemical modification method used in the development of new composite materials based on epoxy binder and natural minerals

Umida ZIYAMUKHAMEDOVA, Dilshod DJUMABAEV, Botirali SHAYMARDANOV

Disposable carbon electrodes as an alternative for the direct voltammetric determination of alkyl phenols from water samples

İulia Gabriela DAVID

Advances in the chemistry of pyrazolopyrazoles

Rizk Elsyad KHIDRE, Hanan Ahmed MOHAMED

Fabrication of layer-by-layer deposited films containing carbon nanotubes and poly(malachite green) as a sensor for simultaneous determination of ascorbic acid, epinephrine, and uric acid

Jahan Bakhsh RAOOF, Reza OJANI, Mehdi BAGHAYERI

Synthesis and characterization of Ni(II) and Cu(II) complexes derived from novel phenolic Mannich bases

Nurgün BÜYÜKKIDAN, Salih ÖZER

Enaminonitriles in heterocyclic synthesis: synthesis and biological evaluation of novel indeno[2,1-b]thiophene derivatives

Ahmed A FADDA, Abd ElGalil M KHALIL, Eman H TAWFIK