TY  - JOUR
A1  - De Sousa Mota, Cristiano
A1  - Diniz, Ana
A1  - Coelho, Catarina
A1  - Santos-Silva, Teresa
A1  - Esmaeeli Moghaddam Tabalvandani, Mariam
A1  - Leimkühler, Silke
A1  - Cabrita, Eurico J.
A1  - Marcelo, Filipa
A1  - Romão, Maria João
T1  - Interrogating the inhibition mechanisms of human aldehyde oxidase by X-ray crystallography and NMR spectroscopy
BT  - the raloxifene case
JF  - Journal of medicinal chemistry / American Chemical Society
N2  - Human aldehyde oxidase (hAOX1) is mainly present in the liver and has an emerging role in drug metabolism, since it accepts a wide range of molecules as substrates and inhibitors. Herein, we employed an integrative approach by combining NMR, X-ray crystallography, and enzyme inhibition kinetics to understand the inhibition modes of three hAOX1 inhibitors-thioridazine, benzamidine, and raloxifene. These integrative data indicate that thioridazine is a noncompetitive inhibitor, while benzamidine presents a mixed type of inhibition. Additionally, we describe the first crystal structure of hAOX1 in complex with raloxifene. Raloxifene binds tightly at the entrance of the substrate tunnel, stabilizing the flexible entrance gates and elucidating an unusual substrate-dependent mechanism of inhibition with potential impact on drug-drug interactions. This study can be considered as a proof-of-concept for an efficient experimental screening of prospective substrates and inhibitors of hAOX1 relevant in drug discovery.
Y1  - 2021
U6  - https://doi.org/10.1021/acs.jmedchem.1c01125
SN  - 0022-2623
SN  - 1520-4804
VL  - 64
IS  - 17
SP  - 13025
EP  - 13037
PB  - American Chemical Society
CY  - Washington
ER  -