Structure-Based Inhibitor Design of Human Hematopoietic Prostaglandin D Synthase

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  • Inoue Tsuyoshi
    Department of Materials Chemistry, Graduate School of Engineering, Osaka University
  • Kai Yasushi
    Department of Materials Chemistry, Graduate School of Engineering, Osaka University
  • Urade Yoshihiro
    (財)大阪バイオサイエンス研究所分子行動生物学部門

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  • ヒト造血器型プロスタグランジンＤ合成酵素の構造に基づく阻害剤の開発
  • ヒト ゾウケツキガタ プロスタグランジン D ゴウセイ コウソ ノ コウゾウ ニ モトヅク ソガイザイ ノ カイハツ

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Abstract

Hematopoietic prostaglandin (PG) D synthase (H-PGDS) catalyzes the isomerization of PGH2 to PGD2, an allergic and inflammatory mediator, in the presence of glutathione (GSH) in mast and Th2 cells. We have determined the crystal structures of the Ca2+- and Mg2+- bound forms of human H-PGDS, revealing the metal activation mechanism, in which Ca2+ or Mg2+ increases its activity to150% of the basal level, with half maximum effective concentrations of 400μM for Ca2+ and 50μM for Mg2+. Especially, we found a four-fold reduction in the Km of the enzyme for GSH in the presence of Mg2+. We also performed the X-ray crystallographic studies of the complex crystals with some inhibitors. Among them HQL-79 is effect with orally treatment with IC50 value of 5.8μM, and three new inhibitors derived from HQL-79 were designed. The complex structures with these inhibitors provide a novel insight into the anti-allergic drug designs.

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