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
Citation:

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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