title: Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors.
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.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Chiba
authors.forename: Jun
authors.initials: J
authors.lastname: Ohwada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Takaaki A
authors.initials: TA
authors.lastname: Fukami
authors.forename: Machiko
authors.initials: M
authors.lastname: Irie
authors.forename: Takaaki
authors.initials: T
authors.lastname: Miura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ohara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koyano
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C023422:7-azaindole dimer; D004791:Enzyme Inhibitors; D007211:Indoles; D011728:Pyridones; D007791:Lactoylglutathione Lyase