Investigation in silico the interaction of oxazolinyl derivatives of [17(20)E]-21-norpregnene with androgen receptor.

  • K.A. Shcherbakov Institute of Biomedical Chemistry, 10 Pogodinskaya str., Moscow 119121, Russia
  • D.S. Shcherbinin Center for Data-Intensive Biomedicine and Biotechnology, Skolkovo Institute of Science and Technology, Moscow, Russia
  • V.A. Kostin Institute of Biomedical Chemistry, Moscow, Russia
  • V.A. Zolottsev Institute of Biomedical Chemistry, Moscow, Russia
  • A.Yu. Misharin Institute of Biomedical Chemistry, Moscow , Russia
  • A.V. Veselovsky Institute of Physiologically Active Compounds, Moscow region, Chernogolovka, Russia
Keywords: prostate cancer; androgen receptor; derivatives of pregna-5,17(20)-diene; docking; molecular dynamics; MM-GBSA method

Abstract

The ability of novel oxazolinyl derivatives of pregna-5,17(20)-diene to interact with the androgen receptor (AR) was investigated using molecular modelling methods. Six new derivatives differed in oxazolinyl radicals in 17 position were used. It was shown that all compounds were able to docked in the ligand-binding domain of AR only when the AR helix-12 was removed. It is suggested that these compounds have antagonistic properties. Results of docking and simulation of molecular dynamics with estimation of binding energy allow to predict that two compounds can be effective AR antagonists.

References

  1. Vasaitis, T.S., Bruno, R.D., & Njar V.C.O. (2011). CYP17 inhibitors for prostate cancer therapy. J. Steroid Biochem. Mol. Biol., 125. 24-30. DOI

  2. Baston, E., & Leroux, F.R. (2007). Inhibitors of Steroidal Cytochrome P450 Enzymes as Targets for Drug Development. Recent Pat. Anti-Cancer Drug. Disc., 2, 31-58. DOI

  3. Bruno, R.D., & Nja,r V.C.O. (2007). Targeting cytochrome P450 enzymes: A new approach in anti-cancer drug development. Bioorgan. Med. Chem., 15, 5047-5060. DOI

  4. de Bono, J.S., Logothetis, C.J., Molina, A., Fizazi, K., North, S., Chu, L., Chi, K.N., Jones, R.J., Goodman, O.B. Jr., Saad, F., StaVurth, J.N., Mainwaring, P., Harland, S., Flaig, T.W., Hutson, T.E., Cheng, T., Patterson, H., Hainsworth, J.D., Ryan, C.J., Sternberg, C.N., Ellard, S.L., Fléchon, A., Saleh, M., Scholz, M., Efstathiou, E,, Zivi, A., Bianchini, D., Loriot, Y., ChieVo, N., Kheoh, T., Haqq, C.M., Scher, H.I., & COU-AA-301 Investigators. (2011). Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med., 364, 1995-2005. DOI

  5. Vasaitis, T., Belosay, A., Schayowitz, A., Khandelwal, A., Chopra, P., Gediya, L.K., Guo, Z., Fang, H.B., Njar, V.C., & Brodie, A.M. (2008). Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17, 20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl) androsta-5,16-diene in prostate cancer. Mol. Cancer Ther., 7, 2348-2357. DOI

  6. Gao, W., Bohl, C.E., & Dalton, J.T. (2005). Chemistry and Structural Biology of Androgen Receptor. Chem. Rev.,105, 3352-702. DOI

  7. Tindall, D., Mohler, J. (eds). Androgen Action in Prostate Cancer. Dordrecht, Heidelberg, London, New York.- Springer - 2009.

  8. Thakur, A., Roy, A., Ghosh, A., Chhabra, M., & Banerjee, S. (2018). Abiraterone acetate in the treatment of prostate cancer. Biomed Pharmacother., 101, 211-218. DOI

  9. Njar, V.C., Brodie, A.M. (2015). Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer. J. Med. Chem., 58, 2077-2087. DOI

  10. Bastos, D.A., & Antonarakis, E.S. (2016). Galeterone for the treatment of advanced prostate cancer: the evidence to date. Drug Des Devel Ther., 10, 2289-2297. DOI

  11. Crona, D.J., Milowsky, M.I., & Whang, Y,E. (2015). Androgen receptor targeting drugs in castration-resistant prostate cancer and mechanisms of resistance. Clin. Pharmacol. Ther., 98(6), 582-589. DOI

  12. Yin, L., & Hu, Q. (2014). CYP17 inhibitors--abiraterone, C17,20-lyase inhibitors and multi-targeting agents. Nat. Rev. Urol., 11(1), 32-42. DOI

  13. Stulov S.V., & Misharin A.Yu. (2012). Synthesis of steroids with nitrogen-containing substituents in ring D. Chemistry of heterocyclic compounds, 1536-1582.

  14. Kuzikov, A.V., Dugin, N.O., Stulov, S.V., Shcherbinin, D.S., Zharkova, M.S., Tkachev, Y.V., Timofeev, V.P., Veselovsky, A.V., Shumyantseva, V.V., & Misharin, A.Y. (2014). Novel oxazolinyl derivatives of pregna-5,17(20)-diene as 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitors. Steroids., 88, 66-71. DOI

  15. Kostin, V.A., Zolottsev, V.A., Kuzikov, A.V., Masamrekh, R.A., Shumyantseva, V.V., Veselovsky, A.V., Stulov, S.V., Novikov, R.A., Timofeev, V.P., & Misharin, A.Y. (2016). Oxazolinyl derivatives of [17(20)E]-21-norpregnene differing in the structure of A and B rings. Facile synthesis and inhibition of CYP17A1 catalytic activity. Steroids, 115, 114-122. DOI

  16. Zolottsev, V.A., Tkachev, Y.V., Latysheva, A.S., Kostin, V.A., Novikov, R.A., Timofeev, V.P., Morozevich, G.E., Kuzikov, A.V., Shumyantseva, V.V., & Misharin, A.Y. (2018). Comparison of [17(20)E]-21-Norpregnene oxazolinyl and benzoxazolyl derivatives as inhibitors of CYP17A1 activity and prostate carcinoma cells growth. Steroids, 129, 24-34. DOI

  17. Stulov, S.V., Mankevich, O.V., Novikov, R.A., Tkachev, Y.V., Timofeev, V.P., Dugin, N.O., Pozdnev, V.F., Fedyushkina, I.V., Scherbinin, D.S., Veselovsky, A.V., & Misharin, A.Yu. (2013) Synthesis and molecular modeling of (4'R)- and (4'S)- 4'-substituted 2'-{[(E)-androst-5-en-17-ylidene]-methyl}oxazolines. Steroids, 78, 521-527. DOI

  18. HyperChem(TM) Professional 7.51, Hypercube, Inc., 1115 NW 4th Street, Gainesville, Florida 32601, USA

  19. James Stewart. MOPAC Home Page. Stewart Computational Chemistry, 2012.

  20. Trott, O., & Olson, A.J. (2010). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 31(2), 455-461.

  21. Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., & Olson, A.J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 30(16), 2785-2791. DOI

  22. Cantin, L., Faucher, F., Couture, J.F., de Jesus-Tran, K.P., Legrand, P., Ciobanu, .LC., Frechette, Y., Labrecque, R., Singh, S.M., Labrie, F., & Breton. R. (2007). Structural characterization of the human androgen receptor ligand-binding domain complexed with EM5744, a rationally designed steroidal ligand bearing a bulky chain directed toward helix 12. J. Biol. Chem., 282(42), 30910-30919. DOI

  23. Laskowski, R.A., & Swindells, M.B. (2011). LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J. Chem. Inf. Model., 51, 2778-2786. DOI

  24. Salomon-Ferrer, R., Case, D.A., & Walker, R.C. (2013). An overview of the Amber biomolecular simulation package. Wiley Interdiscip. Rev. Comput. Mol. Sci., 3(2), 198-210. DOI

  25. Humphrey, W., Dalke, A., & Schulten, K. (1996). VMD: Visual molecular dynamics. J. Mol. Graph., 14(1), 33-38. DOI

  26. Genheden, S., & Ryde, U. (2015). The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin. Drug Discov., 10(5), 449-461. DOI

  27. Davey, R.A., & Grossmann, M. (2016). Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin. Biochem. Rev., 37(1), 3-15.

  28. Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W., & Klein, M.L. (1983) Comparison of simple potential functions for simulating liquid water, J. Chem. Phys., 79(2), 926-935. DOI

  29. Wang, Y., Han, R., Zhang, H., Liu, H., Li, J., Liu, H., & Gramatica, P. (2017) Combined Ligand/Structure-Based Virtual Screening and Molecular Dynamics Simulations of Steroidal Androgen Receptor Antagonists. Biomed. Res. Int., 3572394. DOI

  30. Stulov, S.V., Dugin, N.O., Zharkova, M.S., Shcherbinin, D.S., Kuzikov, A.V., Shumantseva, V.V., Misharin, A.Yu., & Veselovsky, A.V. (2015) Interaction of Novel Oxazoline Derivatives of 17(20) E-pregna-5,17(20)-Diene with Cytochrome P450 17 A1. Bioсhemistry (Moscow) Suppl Ser B: Biomedical Chemistry, 9(2), 114-120. DOI
Published
2018-04-12
Section
Experimental Research