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.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Heterocyclic Compounds, 4 or More Rings , Molecular Docking Simulation , Steroid 17-alpha-Hydroxylase , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Humans , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Steroid 17-alpha-Hydroxylase/chemistryABSTRACT
Aiming the search of novel regulators of lipid metabolism and their potential targets, in this study we performed molecular modeling of eight isomeric 17(20)Z- and 17(20)E-pregna-5,17(20)-dien-21-oyl amides differing in structure of the amide moiety. Analysis of the low energy conformers revealed that all 17(20)E-isomers had three main energy minima (corresponding to values of the dihedral angle theta20,21 (C17 = C20-C21 = 0) to approximately 0 degrees, to approximately 120 degrees and to approximately 240 degrees), the most occupied minimum was found to correspond to theta20,21 to approximately 0 degrees; while 17(20)Z-isomers had either one or two pools of low energy conformations. Molecular docking of these compounds to the ligand-binding site of the nuclear receptor LXRbeta (a potential target) indicates high probability of binding for E-isomers and the absence of that for Z-isomers. Results of the molecular modeling were confirmed by an experiment in which stimulation of triglyceride biosynthesis in Hep G2 cells in the presence of 17(20)E-3beta-hydroxypregna-5,17(20)-dien-21-oyl (hydroxyethyl)amide was demonstrated.
