Mechanisms of allosteric and mixed mode aromatase inhibitors.

ABSTRACT: 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 c

SUBMITTER: Souza SA 

PROVIDER: S-EPMC8341375 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature