X-ray structure of human aldo-keto reductase 1C3 in complex with a bile acid fused tetrazole inhibitor: experimental validation, molecular docking and structural analysis

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F23%3A00569100" target="_blank" >RIV/61388963:_____/23:00569100 - isvavai.cz</a>

Result on the web

<a href="https://doi.org/10.1039/D2MD00387B" target="_blank" >https://doi.org/10.1039/D2MD00387B</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/d2md00387b" target="_blank" >10.1039/d2md00387b</a>

Result language

angličtina

Original language name

X-ray structure of human aldo-keto reductase 1C3 in complex with a bile acid fused tetrazole inhibitor: experimental validation, molecular docking and structural analysis

Original language description

Aldo-keto reductase 1C3 (AKR1C3) catalyzes the reduction of androstenedione to testosterone and reduces the effectiveness of chemotherapeutics. AKR1C3 is a target for treatment of breast and prostate cancer and AKR1C3 inhibition could be an effective adjuvant therapy in the context of leukemia and other cancers. In the present study, steroidal bile acid fused tetrazoles were screened for their ability to inhibit AKR1C3. Four C24 bile acids with C-ring fused tetrazoles were moderate to strong AKR1C3 inhibitors (37-88% inhibition), while B-ring fused tetrazoles had no effect on AKR1C3 activity. Based on a fluorescence assay in yeast cells, these four compounds displayed no affinity for estrogen receptor-alpha, or the androgen receptor, suggesting a lack of estrogenic or androgenic effects. A top inhibitor showed specificity for AKR1C3 over AKR1C2, and inhibited AKR1C3 with an IC50 of similar to 7 mu M. The structure of AKR1C3 center dot NADP(+) in complex with this C-ring fused bile acid tetrazole was determined by X-ray crystallography at 1.4 angstrom resolution, revealing that the C24 carboxylate is anchored to the catalytic oxyanion site (H117, Y55), meanwhile the tetrazole interacts with a tryptophan (W227) important for steroid recognition. Molecular docking predicts that all four top AKR1C3 inhibitors bind with nearly identical geometry, suggesting that C-ring bile acid fused tetrazoles represent a new class of AKR1C3 inhibitors.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/LX22NPO5102" target="_blank" >LX22NPO5102: National institute for cancer research</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

RSC MEDICINAL CHEMISTRY

ISSN

2632-8682

e-ISSN

2632-8682

Volume of the periodical

14

Issue of the periodical within the volume

2

Country of publishing house

GB - UNITED KINGDOM

Number of pages

15

Pages from-to

341-355

UT code for WoS article

000915725200001

EID of the result in the Scopus database

2-s2.0-85149751315