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ID: ALA2203256
Journal: Bioorg Med Chem Lett
Title: Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors.
Authors: Chiba T, Ohwada J, Sakamoto H, Kobayashi T, Fukami TA, Irie M, Miura T, Ohara K, Koyano H.
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.
CiteXplore: 23122816