An efficient steroid pharmacophore-based strategy to identify new aromatase inhibitors.

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Neves MA, Dinis TC, Colombo G, Sa e Melo ML

An efficient steroid pharmacophore-based strategy to identify new aromatase inhibitors.

Eur J Med Chem. 2009 Oct;44(10):4121-7. doi: 10.1016/j.ejmech.2009.05.003. Epub 2009 May 19.

PubMed ID

19500885 [ View in PubMed

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Abstract

Aromatase, an enzyme involved in the conversion of androgens into estrogens, is an important target for the endocrine treatment of breast cancer. Aromatase inhibition is usually achieved with steroids structurally related to the substrate of catalysis or, alternatively, with azole non-steroid compounds. Substituted androstenedione derivatives with Delta(1), Delta(6) and Delta(1,6) unsaturations and 6-alkyl/6-phenyl aliphatic substitutions, are among the most potent steroid aromatase inhibitors known to date. In this paper we have combined the common pharmacophoric and shape features of these molecules into a new pharmacophore model, useful for virtual screening of large compound databases. Small subsets of the best fitting anti-aromatase candidates were extracted from the NCI database and experimentally tested on an in vitro assay with human placental aromatase. New potent aromatase inhibitors were identified such as compounds 8 and 14. Considering the lack of a crystal structure for the aromatase enzyme, this ligand-based method is a valuable tool for the virtual screening of new aromatase inhibitors.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Aminoglutethimide	Cytochrome P450 19A1	IC 50 (nM)	10000	N/A	N/A	Details