Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure-Function Perspective.
Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure-Function Perspective.
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DOI：
10.1021/acs.jmedchem.5b01281
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发表时间：
2016-06-09
影响因子：
7.3
通讯作者：
Egbuta C
中科院分区：
文献类型：
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作者：
Ghosh D;Lo J;Egbuta C
人芳香酶催化雄激素合成雌激素具有高底物特异性。在过去的40年里，芳香化酶一直是一个强烈的抑制剂发现研究的目标，用于预防和治疗雌激素依赖性乳腺癌。所谓的第三代芳香化酶抑制剂（AIs）来曲唑、阿那曲唑和类固醇依西美坦在20世纪90年代末在美国被批准用于雌激素依赖性绝经后乳腺癌。由于缺乏这种独特的P450的实验结构，开发具有更高选择性和更低副作用的更好的ai的努力受到阻碍。2009年发表了从人胎盘中纯化的芳香酶晶体结构，揭示了雄激素特异性活性位点。这种结构重新激活了对这种迷人酶的研究活动，并成为下一代人工智能发现研究的催化剂。在这里，我们从酶的结构-功能关系的角度介绍了人工智能领域的最新发展。
Human aromatase catalyzes the synthesis of estrogen from androgen with high substrate specificity. For the past 40 years, aromatase has been a target of intense inhibitor discovery research for the prevention and treatment of estrogen-dependent breast cancer. The so-called third generation aromatase inhibitors (AIs) letrozole, anastrozole, and the steroidal exemestane were approved in the U.S. in the late 1990s for estrogen-dependent postmenopausal breast cancer. Efforts to develop better AIs with higher selectivity and lower side effects were handicapped by the lack of an experimental structure of this unique P450. The year 2009 marked the publication of the crystal structure of aromatase purified from human placenta, revealing an androgen-specific active site. The structure has reinvigorated research activities on this fascinating enzyme and served as the catalyst for next generation AI discovery research. Here, we present an account of recent developments in the AI field from the perspective of the enzyme’s structure–function relationships.