Interaction of novel oxazoline derivatives of 17(20)e-pregna-5,17(20)-diene with cytochrome P450 17A1

Stulov S.V.1, Dugin N.O.1, Zharkova M.S.1, Shcherbinin D.S.1, Kuzikov A.V.1, Shumyantseva V.V.1, Misharin A.Yu.1, Veselovsky A.V.1

1. Institute of Biomedical Chemistry, Moscow, Russia
Section: Experimental Study
DOI: 10.18097/PBMC20166201038      PubMed Id: 26973185
Year: 2016  Volume: 62  Issue: 1  Pages: 38-44
In order to find novel inhibitors of 17a-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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Keywords: nitrogen-containing derivatives of 17(20)E-pregna-5,17(20)-diene, cytochrome P450 17A1, inhibitors, molecular modeling, electrochemistry, structure-activity relationships

Stulov, S. V., Dugin, N. O., Zharkova, M. S., Shcherbinin, D. S., Kuzikov, A. V., Shumyantseva, V. V., Misharin, A. Yu., Veselovsky, A. V. (2016). Interaction of novel oxazoline derivatives of 17(20)e-pregna-5,17(20)-diene with cytochrome P450 17A1. Biomeditsinskaya Khimiya, 62(1), 38-44.
This paper is also available as the English translation: 10.1134/S1990750815020134
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