Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors

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• 作者：Takashi Chiba ; Jun Ohwada ; Hiroshi Sakamoto ; Takamitsu Kobayashi ; Takaaki A. Fukami ; Machiko Irie ; Takaaki Miura ; Kazuhiro Ohara ; Hiroshi Koyano ; ^{koyanohrs@chugai-pharm.co.jp}
• 关键词：Glyoxalase I (GLO1) ; Structure-based drug design (SBDD) ; N-Hydroxypyridone ; 7-Azaindole
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：15 December, 2012
• 年：2012
• 卷：22
• 期：24
• 页码：7486-7489
• 全文大小：712 K

文摘

We conducted a high throughput screening for glyoxalase I (GLO1) inhibitors and identified 4,6-diphenyl-N-hydroxypyridone as a lead compound. Using a binding model of the lead and public X-ray coordinates of GLO1 enzymes complexed with glutathione analogues, we designed 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones. 7-Azaindole¡¯s 7-nitrogen was expected to interact with a water network, resulting in an interaction with the protein. We validated this inhibitor design by comparing its structure-activity relationship (SAR) with that of corresponding indole derivatives, by analyzing the binding mode with X-ray crystallography and by evaluating its thermodynamic binding parameters.