title: [Interaction of novel oxazoline derivatives of 17(20)e-pregna-5,17(20)-diene with cytochrome P450 17A1].
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.
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: S V
authors.initials: SV
authors.lastname: Stulov
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: N O
authors.initials: NO
authors.lastname: Dugin
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: M S
authors.initials: MS
authors.lastname: Zharkova
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: D S
authors.initials: DS
authors.lastname: Shcherbinin
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: A V
authors.initials: AV
authors.lastname: Kuzikov
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: V V
authors.initials: VV
authors.lastname: Shumyantseva
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: A Yu
authors.initials: AY
authors.lastname: Misharin
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: A V
authors.initials: AV
authors.lastname: Veselovsky
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D062105:Molecular Docking Simulation; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase
keywords: cytochrome P450 17A1; electrochemistry; inhibitors; molecular modeling; nitrogen-containing derivatives of 17(20)E-pregna-5,17(20)-diene; structure-activity relationships