COMPUTER-AIDED DESIGN OF POTENTIAL AROMATASE INHIBITORS BASED ON 1,2,4-TRIAZOLE DERIVATIVES
https://doi.org/10.29235/1561-8323-2018-62-3-281-292
Abstract
Computer-aided design of the high-affinity inhibitors of aromatase based on 1,2,4-triazole derivatives was performed by molecular modeling tools. The potential biological activity of the designed compounds was evaluated by molecular docking and quantum chemistry calculations. As a result, six hits that form a coordinate bond with an iron atom of an enzyme hem and effectively interact with its substrate-binding site were identified. The intermolecular interactions appearing in the structural complexes of these ligands with aromatase were analyzed and the enthalpies of their formation were calculated. Based on the data obtained, the identified compounds were suggested to present good scaffolds for the development of novel effective drugs against breast cancer.
About the Authors
A. M. Andrianov
Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus.
Russian Federation
Russian Federation
Andrianov Alexander Mikhailovich – D. Sc. (Chemistry), Chief researcher.
5/2, Kuprevich Str., 220141.
G. I. Nikolaev
United Institute of Informatics Problems of the National Academy of Sciences of Belarus.
Russian Federation
Russian Federation
Nikolaev Gregory Igorevich – Postgraduate student.
6, Surganov Str., 220072, Minsk.
I. A. Kashyn
United Institute of Informatics Problems of the National Academy of Sciences of Belarus .
Russian Federation
Russian Federation
Kashyn Ivan Aleksandrovich – Ph. D. (Chemistry), Senior researcher.
6, Surganov Str., 220072, Minsk.
Yu. V. Kornoushenko
Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus
Russian Federation
Russian Federation
Kornoushenko Yury Valerievich – Ph. D. (Chemistry), Senior researcher.
5/2, Kuprevich Str., 220141, Minsk.
S. A. Usanov
Institute of Bioorganic Che mistry of the National Academy of Sciences of Belarus
Russian Federation
Russian Federation
Usanov Sergey Aleksandrovich – Corresponding Member, D. Sc. (Chemistry), Professor.
5/2, Kuprevich Str., 220141, Minsk.
References
1. Macedo L. F., Sabnis G., Brodie A. Aromatase inhibitors and breast cancer. Annals of the New York Academy of Sciences, 2009, vol. 1155, no. 1, pp. 162–173. https://doi.org/10.1111/j.1749-6632.2008.03689.x
2. Ghosh D., Griswold J., Erman M., Pangborn W. Structural basis for androgen specifity and oestrogen synthesis in human aromatase. Nature, 2009, vol. 457, no. 7226, pp. 219−223. https://doi.org/10.1038/nature07614
3. Hong Y., Chen S. Aromatase inhibitors: structural features and biochemical characterization. Annals of the New York Academy of Sciences, 2006, vol. 1089, no. 1, pp. 237–251. https://doi.org/10.1196/annals.1386.022
4. Dutta U., Pant K. Aromatase inhibitors: past, present and future in breast cancer therapy. Medical Oncology, 2008, vol. 25, no. 2, pp. 113–124. https://doi.org/10.1007/s12032-007-9019-x
5. Ghosh D., Lo J., Egbuta C. Recent progress in the discovery of next generation inhibitors of aromatase from the strucRecent progress in the discovery of next generation inhibitors of aromatase from the structure–function perspective. Journal of Medicinal Chemistry, 2016, vol. 59, no. 11, pp. 5131–5148. https://doi.org/10.1021/acs.jmedchem.5b01281
6. Schuster D., Laggner C., Steindl T. M., Palusczak A., Hartmann R. W., Langer T. Pharmacophore modeling and in silico screening for new P450 19 (aromatase) inhibitors. Journal of Chemical Information and Modeling, 2006, vol. 46, no. 3, pp. 1301–1311. https://doi.org/10.1021/ci050237k
7. Neves M. A., Dinis T. C., Colombo G., Sá e Melo M. L. Fast three dimensional pharmacophore virtual screening of new potent non-steroid aromatase inhibitors. Journal of Medicinal Chemistry, 2009, vol. 52, no. 1, pp. 143–150. https://doi.org/10.1021/jm800945c
8. Neves M. A., Dinis T. C., Colombo G., Sá e Melo M. L. An efficient steroid pharmacophore-based strategy to identify new aromatase inhibitors. European Journal of Medicinal Chemistry, 2009, vol. 44, no. 10, pp. 4121–4127. https://doi.org/10.1016/j.ejmech.2009.05.003
9. Ghosh D., Griswold J., Erman M., Pangborn W. X-ray structure of human aromatase reveals an androgen-specific active site. Journal of Steroid Biochemistry and Molecular Biology, 2010, vol. 118, no. 4–5, pp. 197–202. https://doi.org/10.1016/j.jsbmb.2009.09.012
10. Prior A. M., Yu X., Park E.-J., Kondratyuk T. P., Lin Y., Pezzuto J. M., Sun D. Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1. Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, no. 24, pp. 5393–5399. https://doi.org/10.1016/j.bmcl.2017.11.010
11. Mojaddami A., Sakhteman A., Fereidoonnezhad M., Faghih Z., Najdian A., Khabnadideh S., Sadeghpour H., Rezaei Z. Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies. Research in Pharmaceutical Sciences, 2017, vol. 12, no. 1, pp. 21–30. https://doi.org/10.4103/1735-5362.199043
12. Akram M., Waratchareeyakul W., Haupenthal J., Hartmann R. W., Schuster D. Pharmacophore Modeling and in Silico/in Vitro Screening for Human Cytochrome P450 11B1 and Cytochrome P450 11B2 Inhibitors. Frontiers in Chemistry, 2017, vol. 5, pp. 104. https://doi.org/10.3389/fchem.2017.00104
13. Kolb H. C., Finn M. G., Sharpless K. B. Click chemistry: Diverse chemical function from a few good reactions. Angewandte Chemie International Edition, 2001, vol. 40, no. 11, pp. 2004–2021. https://doi.org/10.1002/1521-3773(20010601)40:11%3C2004::aid-anie2004%3E3.0.co;2-5
14. Lipinski C. A., Lombardo F., Dominy B. W., Feeney P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 2001, vol. 46, no. 1–3, pp. 3–26. https://doi.org/10.1016/s0169-409x(00)00129-0
15. Kao Y. C., Korzekwa K. R., Laughton C. A., Chen S. Evaluation of the mechanism of aromatase cytochrome P450. European Journal of Biochemistry, 2001, vol. 268, no. 2, pp. 243–251. https://doi.org/10.1046/j.1432-1033.2001.01886.x
Review
Views: 1008
Email this article 