期刊
ANTIOXIDANTS
卷 10, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/antiox10050723
关键词
fluorescence; molecular modeling; cancer cell migration; NADPH oxidases; NO-synthases; in vivo imaging
资金
- CAPES (CAPES/COFECUB French-Brazilian Collaborative Research Grant) [Me917/18]
- CINES resources Occigen made by GENCI (Grand Equipment National de Calcul Intensif) [AP010710343]
Research on specific inhibition of NADPH oxidases (NOX) and NO-synthases (NOS) has attracted great pharmacological interest due to their association with redox stress in tumor cells. The study demonstrated that isolated 2'- and 3'-phosphate isomers of the NADPH analogue NS1 improved the specificity of inhibition by distinguishing between isomeric derivatives. The 2'-phosphate isomer of NS1 showed more pronounced effects on NOS and NOX-dependent physiological responses, with docking and molecular dynamics simulations explaining the specificity at the NADPH site of NOX and NOS.
Specific inhibition of NADPH oxidases (NOX) and NO-synthases (NOS), two enzymes associated with redox stress in tumor cells, has aroused great pharmacological interest. Here, we show how these enzymes distinguish between isomeric 2 '- and 3 '-phosphate derivatives, a difference used to improve the specificity of inhibition by isolated 2 '- and 3 '-phosphate isomers of our NADPH analogue NS1. Both isomers become fluorescent upon binding to their target proteins as observed by in vitro assay and in vivo imaging. The 2 '-phosphate isomer of NS1 exerted more pronounced effects on NOS and NOX-dependent physiological responses than the 3 '-phosphate isomer did. Docking and molecular dynamics simulations explain this specificity at the level of the NADPH site of NOX and NOS, where conserved arginine residues distinguished between the 2 '-phosphate over the 3 '-phosphate group, in favor of the 2 '-phosphate.
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