Inhibition of AKR1Cs by liquiritigenin and the structural basis.

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 C 7 –OH, aided by its nonplanar and compact structure due to the saturation of the C 2 C 3 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. [Display omitted] • Liquiritigenin (LQ) was firstly found to inhibit AKR1Cs which are involved in hormonally dependent cancers. • Crystallographic study revealed LQ is complementary with AKR1C3 active site and forms H-bonds with the catalytic residues. • Comparison of LQ in the crystal structures of AKR1Cs showed a good example of induced-fit ligand conformation changes. [ABSTRACT FROM AUTHOR]