Fast three dimensional pharmacophore virtual screening of new potent non-steroid aromatase inhibitors.

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

Fast three dimensional pharmacophore virtual screening of new potent non-steroid aromatase inhibitors.

J Med Chem. 2009 Jan 8;52(1):143-50. doi: 10.1021/jm800945c.

PubMed ID

19072235 [ View in PubMed

]

Abstract

Suppression of estrogen biosynthesis by aromatase inhibition is an effective approach for the treatment of hormone sensitive breast cancer. Third generation non-steroid aromatase inhibitors have shown important benefits in recent clinical trials with postmenopausal women. In this study we have developed a new ligand-based strategy combining important pharmacophoric and structural features according to the postulated aromatase binding mode, useful for the virtual screening of new potent non-steroid inhibitors. A small subset of promising drug candidates was identified from the large NCI database, and their antiaromatase activity was assessed on an in vitro biochemical assay with aromatase extracted from human term placenta. New potent aromatase inhibitors were discovered to be active in the low nanomolar range, and a common binding mode was proposed. These results confirm the potential of our methodology for a fast in silico high-throughput screening of potent non-steroid aromatase inhibitors.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Letrozole	Cytochrome P450 19A1	IC 50 (nM)	6.1	N/A	N/A	Details
Letrozole	Cytochrome P450 19A1	Ki (nM)	2.2	N/A	N/A	Details