Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2
| Autor: | Kelin Li, Jeffrey Aubé, Caleb D. Vogt, Rahul Yadav, Emily E. Scott, Charlie Fehl |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Steric effects endocrine system urologic and male genital diseases Article 03 medical and health sciences Prostate cancer Catalytic Domain Drug Discovery medicine Cytochrome P-450 Enzyme Inhibitors Humans biology Chemistry Active site Cytochrome P450 Steroid 17-alpha-Hydroxylase medicine.disease Molecular Docking Simulation 030104 developmental biology Biochemistry Docking (molecular) CYP17A1 Drug Design biology.protein Molecular Medicine Structure based Androstenes Steroid 21-Hydroxylase Selectivity |
| DOI: | 10.17615/n6b4-6v84 |
| Popis: | Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site. The best analogs increased selectivity of CYP17A1 inhibition up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization with CYP17A1 validated the intended new contacts with CYP17A1 active site residues. Docking these analogs into CYP21A2 identified steric clashes that likely underlie decreased binding and CYP21A2 inhibition. Overall, these analogs may offer a clinical advantage in the form of reduced side effects. |
| Databáze: | OpenAIRE |
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