In silico analyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay-Sachs disease

Atsushi Kato*, Izumi Nakagome, Shinpei Nakagawa, Kyoko Kinami, Isao Adachi, Sarah F. Jenkinson, Jérôme Désiré, Yves Blériot, Robert J. Nash, George W.J. Fleet, Shuichi Hirono

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

21 被引用数 (Scopus)

抄録

The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favorable cation-π interaction with Trp460. Among them, DMDP amide (6) proved to be the most potent competitive inhibitor with a Ki value of 0.041 μM. We analyzed the dynamic properties of both DMDP amide (6) and DNJNAc (1) in aqueous solution using molecular dynamics (MD) calculations; the distance of the interaction between Asp322 and 3-OH and Glu323 and 6-OH was important for stable interactions with Hex A, reducing fluctuations in the plasticity of the active site. DMDP amide (6) dose-dependently increased intracellular Hex A activity in the G269S mutant cells and restored Hex A activity up to approximately 43% of the wild type level; this effect clearly exceeded the border line treatment for Tay-Sachs disease, which is regarded as 10-15% of the wild type level. This is a significantly greater effect than that of pyrimethamine, which is currently in Phase 2 clinical trials. DMDP amide (6), therefore, represents a new promising pharmacological chaperone candidate for the treatment of Tay-Sachs disease.

本文言語英語
ページ(範囲)9297-9304
ページ数8
ジャーナルOrganic and Biomolecular Chemistry
15
44
DOI
出版ステータス出版済み - 2017

ASJC Scopus 主題領域

  • 生化学
  • 物理化学および理論化学
  • 有機化学

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