Rational Design of Potent Inhibitors of hDHODH with in Vivo Anti-arthritic Activity

This work presented a series of benzylidenehydrazinyl-substituted thiazole inhibitors to suppress the bioactivity of hDHODH. Compound 19 displayed the lowest IC50 value among these compounds, with notable anti-arthritic efficacy and acceptable pharmacokinetic profiles in vivo. These results suggest the potential of 19 for application as an immunosuppressive agent targeting hDHODH. More importantly, water-bridged interactions between the ligands and hDHODH were identified in the three X-ray structures solved in this study. Two robust bridging water molecules co-occurred with the ligands to help maintain their bioactive conformations by generating a strong water-mediated hydrogen bond network between the flexible 2-(2-methylenehydrazinyl)thiazole linker and hDHODH. The locations and H-bonding patterns of the water molecules are highly complementary with the polar moieties of the ligands in the ubiquinone-binding site of hDHODH and should be considered in future drug design and optimization workflows targeting hDHODH.

Sci. Rep. , 2015. 5 : 14836

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