Inhibition of AKR1Cs by liquiritigenin and the structural basis

Huan Liu; Ziqing Yao; Mingna Sun; Chao Zhang; Yi-You Huang; Hai-Bin Luo; Deyan Wu; Xuehua Zheng

doi:10.1016/j.cbi.2023.110654

Inhibition of AKR1Cs by liquiritigenin and the structural basis

Chem Biol Interact. 2023 Nov 1:385:110654. doi: 10.1016/j.cbi.2023.110654. Epub 2023 Sep 2.

Authors

Huan Liu¹, Ziqing Yao¹, Mingna Sun¹, Chao Zhang¹, Yi-You Huang², Hai-Bin Luo², Deyan Wu³, Xuehua Zheng⁴

Affiliations

¹ Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
² Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, Hainan, China.
³ Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, Hainan, China. Electronic address: wudeyan@hainanu.edu.cn.
⁴ Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. Electronic address: zhengxh23@gzhmu.edu.cn.

PMID: 37666442
DOI: 10.1016/j.cbi.2023.110654

Abstract

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.

Keywords: AKR1Cs; Crystal structures; Inhibition; Liquiritigenin; Selectivity.