活体和体外研究证实，甘草中主要活性成分甘草素（LQ）具有抗肿瘤作用。然而，LQ是如何减弱或抑制肿瘤生长的机制还不完全清楚。在此，我们报告了LQ和其他六个黄烷酮类似物对AKR1Cs（AKR1C1，AKR1C2 和AKR1C3）的酶抑制作用，这些酶与前列腺癌、乳腺癌和抗癌药物耐药性相关。晶体学研究揭示了AKR1C3通过与活性位点的亲和力和由C7-OH形成的催化位点中的氢键网络而抑制LQ，这得益于其由于C2C3双键的饱和而呈非平面和紧凑结构。在AKR1C1和AKR1C3的结构中对LQ构象的比较显示了感应适应构象变化，这解释了LQ缺乏对异构体的选择性。我们的研究结果将有助于更好地理解LQ对激素依赖性肿瘤的抗肿瘤作用以及选择性AKR1Cs抑制剂的合理设计。版权所有 © 2023。Elsevier B.V.出版。

In vivo and in vitro studies have confirmed that liquiritigenin (LQ), the primary active component of licorice, acts as an antitumor agent. However, how LQ diminishes or inhibits tumor growth is not fully understood. Here, we report the enzymatic inhibition of LQ and six other flavanone analogues towards AKR1Cs (AKR1C1, AKR1C2 and AKR1C3), which are involved in prostate cancer, breast cancer, and resistance of anticancer drugs. Crystallographic studies revealed AKR1C3 inhibition of LQ is related to its complementarity with the active site and the hydrogen bonds net in the catalytic site formed through C7-OH, aided by its nonplanar and compact structure due to the saturation of the C2C3 double bond. Comparison of the LQ conformations in the structures of AKR1C1 and AKR1C3 revealed the induced-fit conformation changes, which explains the lack of isoform selectivity of LQ. Our findings will be helpful for better understanding the antitumor effects of LQ on hormonally dependent cancers and the rational design of selective AKR1Cs inhibitors.Copyright © 2023. Published by Elsevier B.V.