title: Discovery of a new type inhibitor of human glyoxalase I by myricetin-based 4-point pharmacophore.
abstract: The human glyoxalase I (hGLO I), which is a rate-limiting enzyme in the pathway for detoxification of apoptosis-inducible methylglyoxal (MG), has been expected as an attractive target for the development of new anti-cancer drugs. We have previously identified a natural compound myricetin as a substrate transition-state (Zn(2+)-bound MG-glutathione (GSH) hemithioacetal) mimetic inhibitor of hGLO I. Here, we constructed a hGLO I/inhibitor 4-point pharmacophore based on the binding mode of myricetin to hGLO I. Using this pharmacophore, in silico screening of chemical library was performed by docking study. Consequently, a new type of compound, which has a unique benzothiazole ring with a carboxyl group, named TLSC702, was found to inhibit hGLO I more effectively than S-p-bromobenzylglutathione (BBG), a well-known GSH analog inhibitor. The computational simulation of the binding mode indicates the contribution of Zn(2+)-chelating carboxyl group of TLSC702 to the hGLO I inhibitory activity. This implies an important scaffold-hopping of myricetin to TLSC702. Thus, TLSC702 may be a valuable seed compound for the generation of a new lead of anti-cancer pharmaceuticals targeting hGLO I.
authors.affiliation: Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takasawa
authors.forename: Akinobu
authors.initials: A
authors.lastname: Tao
authors.forename: Kazunori
authors.initials: K
authors.lastname: Saeki
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Shionozaki
authors.forename: Ryo
authors.initials: R
authors.lastname: Tanaka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Uchiro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yoshimori
authors.forename: Sei-Ichi
authors.initials: S
authors.lastname: Tanuma
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry*; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D011994:Recombinant Proteins; C040015:myricetin; D007791:Lactoylglutathione Lyase