Aromatase (Cyp19) catalyzes the last biosynthetic step of estrogens in mammals and is a primary drug target for hormone-related breast cancer. However, treatment with aromatase inhibitors is often associated with adverse effects and drug resistance. In this study, we used virtual screening targeting a predicted cytochrome P450 reductase binding site on aromatase to discover four novel non-steroidal aromatase inhibitors. The inhibitors have potencies comparable to the noncompetitive tamoxifen metabolite, endoxifen. Our two most potent inhibitors, AR11 and AR13, exhibit both mixed-type and competitive-type inhibition. The cytochrome P450 reductase-Cyp19 coupling interface likely acts as a transient binding site. Our modeling shows that our inhibitors bind better at different sites near the catalytic site. Our results predict the location of multiple ligand binding sites on aromatase. The combination of modeling and experimental results supports the important role of the reductase binding interface as a low affinity, promiscuous ligand binding site. Our new inhibitors may be useful as alternative chemical scaffolds that may show different adverse effects profiles than current clinically used aromatase inhibitors.

中文翻译：

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变构和混合模式芳香酶抑制剂的作用机理

芳香酶（Cyp19）催化哺乳动物中雌激素的最后生物合成步骤，是激素相关乳腺癌的主要药物靶标。但是，用芳香酶抑制剂治疗通常与不良反应和耐药性有关。在这项研究中，我们使用针对芳香酶上预测的细胞色素P450还原酶结合位点的虚拟筛选来发现四种新型非甾体芳香酶抑制剂。该抑制剂的功效可与非竞争性他莫昔芬代谢物endoxifen相媲美。我们的两种最有效的抑制剂AR11和AR13表现出混合型和竞争型抑制。细胞色素P450还原酶-Cyp19偶联界面可能充当瞬时结合位点。我们的模型表明，我们的抑制剂在催化部位附近的不同部位结合更好。我们的结果预测了芳香化酶上多个配体结合位点的位置。建模和实验结果的组合支持还原酶结合界面作为低亲和力，混杂的配体结合位点的重要作用。我们的新型抑制剂可用作替代化学支架，与目前临床使用的芳香化酶抑制剂相比，可能显示出不同的不良反应。