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Rational Design of Benzylidenehydrazinyl-Substituted Thiazole Derivatives as Potent Inhibitors of Human Dihydroorotate Dehydrogenase with in Vivo Anti-arthritic Activity.

Li S, Luan G, Ren X, Song W, Xu L, Xu M, Zhu J, Dong D, Diao Y, Liu X, Zhu L, Wang R, Zhao Z, Xu Y, Li H - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.

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.

No MeSH data available.


Related in: MedlinePlus

Analysis of the structural water molecules at the ubiquinone-binding site of hDHODH.(A) Water-bridging hydrogen bond network. Three X-ray crystal structures solved in this study are aligned together (purple ribbon) and the corresponding ligand are displayed as thin cyan sticks. Interfacial water molecules of 4LS0 (lightblue), 4LS1 (lightpink) and 4LS2 (palegreen) are shown as round balls. Hydrogen bonds are rendered as yellow dashed lines. (B) Distributions of the buried water molecules. Besides the three structures, all the other 32 crystal structures of hDHODH deposited in the Protein Data Bank previously are aligned together, and their buried water molecules are colored red.
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f4: Analysis of the structural water molecules at the ubiquinone-binding site of hDHODH.(A) Water-bridging hydrogen bond network. Three X-ray crystal structures solved in this study are aligned together (purple ribbon) and the corresponding ligand are displayed as thin cyan sticks. Interfacial water molecules of 4LS0 (lightblue), 4LS1 (lightpink) and 4LS2 (palegreen) are shown as round balls. Hydrogen bonds are rendered as yellow dashed lines. (B) Distributions of the buried water molecules. Besides the three structures, all the other 32 crystal structures of hDHODH deposited in the Protein Data Bank previously are aligned together, and their buried water molecules are colored red.

Mentions: In each of the crystal structures of the three complexes derived in our study, an unexpected water bridging pattern was discovered (Fig. 4A). Figure 4B presents the alignment of all 32 reported protein-ligand complex structures of hDHODH deposited in the Protein Data Bank (Supplementary Information Table S2), with the addition of the 3 structures solved in this study. In total, there are 43 interfacial water molecules clustered into four positions in the ubiquinone-binding site of these 35 crystal structures, of which 58.1% are located in the P1 position and 23.3% are located in the P2 position. Of the five water molecules at the P3 position, three were identified in this study. In addition, two water molecules were observed at the P4 position for the first time in this study.


Rational Design of Benzylidenehydrazinyl-Substituted Thiazole Derivatives as Potent Inhibitors of Human Dihydroorotate Dehydrogenase with in Vivo Anti-arthritic Activity.

Li S, Luan G, Ren X, Song W, Xu L, Xu M, Zhu J, Dong D, Diao Y, Liu X, Zhu L, Wang R, Zhao Z, Xu Y, Li H - Sci Rep (2015)

Analysis of the structural water molecules at the ubiquinone-binding site of hDHODH.(A) Water-bridging hydrogen bond network. Three X-ray crystal structures solved in this study are aligned together (purple ribbon) and the corresponding ligand are displayed as thin cyan sticks. Interfacial water molecules of 4LS0 (lightblue), 4LS1 (lightpink) and 4LS2 (palegreen) are shown as round balls. Hydrogen bonds are rendered as yellow dashed lines. (B) Distributions of the buried water molecules. Besides the three structures, all the other 32 crystal structures of hDHODH deposited in the Protein Data Bank previously are aligned together, and their buried water molecules are colored red.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4595849&req=5

f4: Analysis of the structural water molecules at the ubiquinone-binding site of hDHODH.(A) Water-bridging hydrogen bond network. Three X-ray crystal structures solved in this study are aligned together (purple ribbon) and the corresponding ligand are displayed as thin cyan sticks. Interfacial water molecules of 4LS0 (lightblue), 4LS1 (lightpink) and 4LS2 (palegreen) are shown as round balls. Hydrogen bonds are rendered as yellow dashed lines. (B) Distributions of the buried water molecules. Besides the three structures, all the other 32 crystal structures of hDHODH deposited in the Protein Data Bank previously are aligned together, and their buried water molecules are colored red.
Mentions: In each of the crystal structures of the three complexes derived in our study, an unexpected water bridging pattern was discovered (Fig. 4A). Figure 4B presents the alignment of all 32 reported protein-ligand complex structures of hDHODH deposited in the Protein Data Bank (Supplementary Information Table S2), with the addition of the 3 structures solved in this study. In total, there are 43 interfacial water molecules clustered into four positions in the ubiquinone-binding site of these 35 crystal structures, of which 58.1% are located in the P1 position and 23.3% are located in the P2 position. Of the five water molecules at the P3 position, three were identified in this study. In addition, two water molecules were observed at the P4 position for the first time in this study.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.

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.

No MeSH data available.


Related in: MedlinePlus