Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors.
Article Details
- CitationCopy to clipboard
Chiba T, Ohwada J, Sakamoto H, Kobayashi T, Fukami TA, Irie M, Miura T, Ohara K, Koyano H
Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors.
Bioorg Med Chem Lett. 2012 Dec 15;22(24):7486-9. doi: 10.1016/j.bmcl.2012.10.045. Epub 2012 Oct 17.
- PubMed ID
- 23122816 [ View in PubMed]
- Abstract
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.