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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

X-ray structure determination of hDHODH in complex with 7 (PDB ID: 4LS0).(A) Overview of the structure of hDHODH in complex with compound 7. The receptor is shown in cartoon with the large C-terminal domain colored red and the small N-terminal domain colored purple. Flavin mononucleotide (FMN) and orotate (ORO) are displayed as yellow sticks. Compound 7 is rendered as cyan surface. (B) Detailed description of the ubiquinone-binding site. The hydrophilic pockets are highlighted with red dashed lines, and the hydrophobic ones are marked with white dashed lines. Critical residues are represented as thin green sticks. Oxygen atoms are colored red and nitrogen atoms blue. Water molecules are depicted as red balls. Hydrogen bonds are shown as yellow dashed lines.
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f2: X-ray structure determination of hDHODH in complex with 7 (PDB ID: 4LS0).(A) Overview of the structure of hDHODH in complex with compound 7. The receptor is shown in cartoon with the large C-terminal domain colored red and the small N-terminal domain colored purple. Flavin mononucleotide (FMN) and orotate (ORO) are displayed as yellow sticks. Compound 7 is rendered as cyan surface. (B) Detailed description of the ubiquinone-binding site. The hydrophilic pockets are highlighted with red dashed lines, and the hydrophobic ones are marked with white dashed lines. Critical residues are represented as thin green sticks. Oxygen atoms are colored red and nitrogen atoms blue. Water molecules are depicted as red balls. Hydrogen bonds are shown as yellow dashed lines.

Mentions: Compound 7, a benzylidenehydrazinyl-substituted thiazole derivative, was first identified in a hierarchical structure-based virtual screen by our group as a potent hDHODH inhibitors with an IC50 value of 0.365 μM6. To elucidate the binding mode of 7 and promote the structure-based development of hDHODH inhibitors of this series, compound 7 was co-crystallized with hDHODH, yielding X-ray structures that diffracted to 2.07 Å. The coordinates of the crystal structure have been deposited in the Protein Data Bank with PDB ID code 4LS0. The X-ray structure of 7 and hDHODH reveals that the formyl-substituted phenyl ring moiety of 7 is located at the inner region of the ubiquinone-binding pocket of hDHODH. A hydrogen bond is observed between the oxygen atom of the aldehyde group of 7 and the guanidine group of Arg136 at subsite S2 (Fig. 2). Two buried water molecules (W627 and W660) in this hydrophilic region form a complicated water-bridging hydrogen bond network with the ligand and residues Gln47, Arg136 and Thr360. More specifically, W627 forms hydrogen bonds with the sidechain nitrogen atom of Gln47 and the sidechain oxygen atom of Thr360, while W660 is more versatile and participates in the formation of four hydrogen bonds with the sidechain nitrogen atom of Gln47, the backbone oxygen atom of Thr360, the oxygen atom of the formyl group of 7, and the secondary amine nitrogen atom of the hydrazine group of 7. Another structural water molecule, W661, is located near the thiazole moiety and forms a bridge between the nitrogen atom of the thiazole group, the secondary amine of the hydrazine moiety and the carbonyl oxygen atom of residue Ala55. Thus, W661 not only enhances the intramolecular interactions within 7, but also participates in polar interactions between the ligand and hDHODH within the hydrophobic subsite S1. In addition to the hydrogen bond interactions in the hydrophilic region, the hydrophobic interactions between 7 and hDHODH near the entrance of the ubiquinone-binding site (S1, Fig. 2) are also of crucial importance. Because the 4-phenyl-thiazole moiety extends to the entrance of the pocket and fits the pocket shape well, hydrophobic effects and VDW interactions occur between the 4-phenyl-thiazol moiety and residues Leu42, Met43, Leu46, Leu58, Phe62, Leu68, Phe98 and Met111.


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)

X-ray structure determination of hDHODH in complex with 7 (PDB ID: 4LS0).(A) Overview of the structure of hDHODH in complex with compound 7. The receptor is shown in cartoon with the large C-terminal domain colored red and the small N-terminal domain colored purple. Flavin mononucleotide (FMN) and orotate (ORO) are displayed as yellow sticks. Compound 7 is rendered as cyan surface. (B) Detailed description of the ubiquinone-binding site. The hydrophilic pockets are highlighted with red dashed lines, and the hydrophobic ones are marked with white dashed lines. Critical residues are represented as thin green sticks. Oxygen atoms are colored red and nitrogen atoms blue. Water molecules are depicted as red balls. Hydrogen bonds are shown as yellow dashed lines.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: X-ray structure determination of hDHODH in complex with 7 (PDB ID: 4LS0).(A) Overview of the structure of hDHODH in complex with compound 7. The receptor is shown in cartoon with the large C-terminal domain colored red and the small N-terminal domain colored purple. Flavin mononucleotide (FMN) and orotate (ORO) are displayed as yellow sticks. Compound 7 is rendered as cyan surface. (B) Detailed description of the ubiquinone-binding site. The hydrophilic pockets are highlighted with red dashed lines, and the hydrophobic ones are marked with white dashed lines. Critical residues are represented as thin green sticks. Oxygen atoms are colored red and nitrogen atoms blue. Water molecules are depicted as red balls. Hydrogen bonds are shown as yellow dashed lines.
Mentions: Compound 7, a benzylidenehydrazinyl-substituted thiazole derivative, was first identified in a hierarchical structure-based virtual screen by our group as a potent hDHODH inhibitors with an IC50 value of 0.365 μM6. To elucidate the binding mode of 7 and promote the structure-based development of hDHODH inhibitors of this series, compound 7 was co-crystallized with hDHODH, yielding X-ray structures that diffracted to 2.07 Å. The coordinates of the crystal structure have been deposited in the Protein Data Bank with PDB ID code 4LS0. The X-ray structure of 7 and hDHODH reveals that the formyl-substituted phenyl ring moiety of 7 is located at the inner region of the ubiquinone-binding pocket of hDHODH. A hydrogen bond is observed between the oxygen atom of the aldehyde group of 7 and the guanidine group of Arg136 at subsite S2 (Fig. 2). Two buried water molecules (W627 and W660) in this hydrophilic region form a complicated water-bridging hydrogen bond network with the ligand and residues Gln47, Arg136 and Thr360. More specifically, W627 forms hydrogen bonds with the sidechain nitrogen atom of Gln47 and the sidechain oxygen atom of Thr360, while W660 is more versatile and participates in the formation of four hydrogen bonds with the sidechain nitrogen atom of Gln47, the backbone oxygen atom of Thr360, the oxygen atom of the formyl group of 7, and the secondary amine nitrogen atom of the hydrazine group of 7. Another structural water molecule, W661, is located near the thiazole moiety and forms a bridge between the nitrogen atom of the thiazole group, the secondary amine of the hydrazine moiety and the carbonyl oxygen atom of residue Ala55. Thus, W661 not only enhances the intramolecular interactions within 7, but also participates in polar interactions between the ligand and hDHODH within the hydrophobic subsite S1. In addition to the hydrogen bond interactions in the hydrophilic region, the hydrophobic interactions between 7 and hDHODH near the entrance of the ubiquinone-binding site (S1, Fig. 2) are also of crucial importance. Because the 4-phenyl-thiazole moiety extends to the entrance of the pocket and fits the pocket shape well, hydrophobic effects and VDW interactions occur between the 4-phenyl-thiazol moiety and residues Leu42, Met43, Leu46, Leu58, Phe62, Leu68, Phe98 and Met111.

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