Neves Marco A C, Dinis Teresa C P, Colombo Giorgio, Sá e Melo M Luisa
Faculdade de Farmacia, Laboratorio de Quimica Farmaceutica, Centro de Estudos Farmaceuticos, Universidade de Coimbra, Coimbra, Portugal.
J Med Chem. 2009 Jan 8;52(1):143-50. doi: 10.1021/jm800945c.
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.
通过芳香酶抑制来抑制雌激素生物合成是治疗激素敏感性乳腺癌的一种有效方法。第三代非甾体芳香酶抑制剂在最近针对绝经后女性的临床试验中显示出重要益处。在本研究中，我们根据假定的芳香酶结合模式，开发了一种结合重要药效基团和结构特征的新配体策略，可用于虚拟筛选新的强效非甾体抑制剂。从庞大的美国国立癌症研究所数据库中识别出一小部分有前景的候选药物，并通过用人足月胎盘提取的芳香酶进行体外生化测定来评估它们的抗芳香酶活性。发现新的强效芳香酶抑制剂在低纳摩尔范围内具有活性，并提出了一种共同的结合模式。这些结果证实了我们的方法在快速计算机高通量筛选强效非甾体芳香酶抑制剂方面的潜力。
