Abstract
In order to find novel inhibitors of 17α-hydroxylase-17,20-lyase (cytochrome P450 17A1, CYP17A1), a key enzyme of biosynthesis of androgens, molecular docking of six new oxazoline-containing derivatives 17(20)E-pregna-5,17(20)-diene has been carried out to the active site of the crystal structure of CYP17A1 (pdb 3ruk). Results of this study indicate that: (1) complex formation of docked compounds with CYP17A1 causes their isomerization in energetically less favorable 17(20)Z-isomer; (2) the localization of the steroid moiety of all compounds in the active site is basically the same; (3) the structure of the oxazoline moiety significantly influences its position relative to heme as well as the energy of complex formation; (4) coordination of the nitrogen atom of the oxazoline moiety and the heme iron is only possible in the 17(20)Z-conformation with anti oriented double bonds 17(20), and C=N; (5) the presence of two substituents at C4′ of the oxazoline moiety significantly impairs ligand binding; (6) oxazoline- and benzoxazole-containing derivatives 17(20)E-pregna-5,17(20)-diene can effectively inhibit the catalytic activity CYP17A1 and may be of interest as a basis for the development of new drugs for the treatment of androgen-dependent cancer.
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Original Russian Text © S.V. Stulov, N.O. Dugin, M.S. Zharkova, D.S. Shcherbinin, A.V. Kuzikov, V.V. Shumantseva, A.Yu. Misharin, A.V. Veselovsky, 2015, published in Biomeditsinskaya Khimiya.
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Stulov, S.V., Dugin, N.O., Zharkova, M.S. et al. Interaction of novel oxazoline derivatives of 17(20)E-pregna-5,17(20)-diene with cytochrome P450 17A1. Biochem. Moscow Suppl. Ser. B 9, 114–120 (2015). https://doi.org/10.1134/S1990750815020134
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DOI: https://doi.org/10.1134/S1990750815020134