Modified bile acids and androstanes—Novel promising inhibitors of human cytochrome P450 17A1
| Autor: | Suzana Jovanović-Šanta, Marina P. Savić, Ljubica Grbović, Tatsiana Cherkesova, Yaraslau U. Dzichenka, A. V. Yantsevich, Sergey A. Usanov, Michail Shapira |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Endocrinology Diabetes and Metabolism medicine.medical_treatment Clinical Biochemistry Ligands Biochemistry Steroid Bile Acids and Salts Hydroxylation Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology Cytochrome P-450 Enzyme System medicine Cytochrome P-450 Enzyme Inhibitors Humans CYP17A1 Inhibitor Molecular Biology Progesterone chemistry.chemical_classification biology Steroid 17-alpha-Hydroxylase Cytochrome P450 Cell Biology Enzyme assay 030104 developmental biology Enzyme chemistry CYP17A1 030220 oncology & carcinogenesis biology.protein Molecular Medicine Androstane Androstanes |
| Zdroj: | The Journal of Steroid Biochemistry and Molecular Biology. 205:105777 |
| ISSN: | 0960-0760 |
| DOI: | 10.1016/j.jsbmb.2020.105777 |
| Popis: | Cytochromes P450 are key enzymes for steroid hormone biosynthesis in human body. They are considered as targets for the screening of novel high efficient drugs. The results of screening of bile acids and androstane derivatives toward human recombinant steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are presented in this paper. A group of steroids, binding with micromolar or submicromolar affinity (in a range from 9 μM - less than 0.1 μM), was identified. Results presented here showed that these steroidal compounds are able to decrease rate of hydroxylation of essential CYP17A1 substrate - progesterone, while some compounds completely inhibited enzyme activity. Structure-activity relationship (SAR) analysis based on in vitro and in silico studies showed that high affinity of the enzyme to bile acids derivatives is correlated with side chain hydrophobicity and presence of hydroxyl or keto group at C3 position. From the other side, bile acid-derived compounds with more polar side chain or substituents at C7 and C12 positions possess higher Kd values. Among androstane-derived steroids couple of Δ5-steroids with hydroxyl group at C3 position, as well as 16,17-secosteroids, were found to be high affinity ligands of this enzyme. The data obtained could be useful for the design of novel highly efficient inhibitors of CYP17A1, since the bile acids-derived compounds are for first time recognized as effective CYP17A1 inhibitors. |
| Databáze: | OpenAIRE |
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