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

   


1. Institute of Biomedical Chemistry, Moscow, Russia
Type: Experimental study
DOI: 10.18097/PBMC20166201038      UDK: 547.92.057      PubMed Id: 26973185
Year: 2016 vol: 62  issue:1  pages: 38-44
Abstract: 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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Reference: Stulov S.V., Dugin N.O., Zharkova M.S., Shcherbinin D.S., Kuzikov A.V., Shumyantseva V.V., Misharin A.Yu., Veselovsky A.V., Interaction of novel oxazoline derivatives of 17(20)e-pregna-5,17(20)-diene with cytochrome P450 17A1, Biomeditsinskaya khimiya, 2016, vol: 62(1), 38-44.
This paper is also available as the English translation:10.1134/S1990750815020134
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