Abstract |
Human dihydroorotate dehydrogenase (hDHODH) is an attractive therapeutic target for the treatment of rheumatoid arthritis, transplant rejection and other autoimmune diseases. Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range. Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo. Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold. This work not only elucidates promising scaffolds targeting hDHODH for the treatment of rheumatoid arthritis, but also demonstrates that the water-mediated hydrogen bond interaction is an important factor in molecular design and optimization.
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Authors | Shiliang Li, Guoqin Luan, Xiaoli Ren, Wenlin Song, Liuxin Xu, Minghao Xu, Junsheng Zhu, Dong Dong, Yanyan Diao, Xiaofeng Liu, Lili Zhu, Rui Wang, Zhenjiang Zhao, Yufang Xu, Honglin Li |
Journal | Scientific reports
(Sci Rep)
Vol. 5
Pg. 14836
(Oct 07 2015)
ISSN: 2045-2322 [Electronic] England |
PMID | 26443076
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Dihydroorotate Dehydrogenase
- Enzyme Inhibitors
- Thiazoles
- Oxidoreductases Acting on CH-CH Group Donors
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Topics |
- Animals
- Arthritis, Experimental
(drug therapy, enzymology)
- Crystallography, X-Ray
- Dihydroorotate Dehydrogenase
- Dose-Response Relationship, Drug
- Drug Design
- Enzyme Inhibitors
(chemistry, pharmacology)
- Humans
- Hydrogen Bonding
- Male
- Models, Molecular
- Molecular Structure
- Oxidoreductases Acting on CH-CH Group Donors
(antagonists & inhibitors)
- Rats
- Rats, Wistar
- Structure-Activity Relationship
- Thiazoles
(chemistry)
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