Probing the binding pocket of the active site of aromatase with 2-phenylaliphatic androsta-1,4-diene-3,17-dione steroids
| Autor: | Madoka Takahashi, Mitsuteru Numazawa, Kouwa Yamashita |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Time Factors Stereochemistry medicine.medical_treatment Clinical Biochemistry Biochemistry Substrate Specificity Steroid chemistry.chemical_compound Aromatase Endocrinology Catalytic Domain medicine Humans Moiety Androstenedione Molecular Biology Pharmacology chemistry.chemical_classification Trifluoromethyl biology Aromatase Inhibitors Chemistry Organic Chemistry Active site Androstadienes Enzyme Activation Kinetics Enzyme biology.protein Cysteine |
| Zdroj: | Steroids. 75:330-337 |
| ISSN: | 0039-128X |
| DOI: | 10.1016/j.steroids.2010.01.008 |
| Popis: | A series of 2-phenylaliphatic-substituted androsta-1,4-diene-3,17-diones (6) as well as their androstenedione derivatives (5) were synthesized as aromatase inhibitors to gain insights of structure–activity relationships of varying the alkyl moiety (C1 to C4) of the 2-phenylaliphatic substituents as well as introducing a methyl- or trifluoromethyl function to p-position of a phenethyl moiety to the inhibitory activity. The inhibitors examined showed a competitive type inhibition. The 2-phenpropylandrosta-1,4-diene 6c was the most powerful inhibitor (Ki: 16.1 nM) among them. Compounds 6c along with the phenethyl derivative 6b caused a time-dependent inactivation of aromatase (kinact: 0.0293 and 0.0454 min−1 for 6b and 6c, respectively). The inactivation was prevented by the substrate androstenedione, and no significant effect of l -cysteine on the inactivation was observed in each case. Molecular docking of the phenpropyl compound 6c to aromatase was conducted to demonstrate that the phenpropyl group orients to a hydrophobic binding pocket in the active site to result in the formation of thermodynamically stable enzyme–inhibitor complex. |
| Databáze: | OpenAIRE |
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