Discovery of a new type inhibitor of human glyoxalase I by myricetin-based 4-point pharmacophore

作者：Takasawa Ryoko; Tao Akinobu; Saeki Kazunori; Shionozaki Nobuhiro; Tanaka Ryo; Uchiro Hiromi; Takahashi Satoshi; Yoshimori Atsushi; Tanuma Sei ichi^*

来源：Bioorganic & Medicinal Chemistry Letters, 2011, 21(14): 4337-4342.

DOI：10.1016/j.bmcl.2011.05.046

• Glyoxalase I
• Inhibitor
• Pharmacophore modeling
• In silico screening
• Structure-activity relationship

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.

• 出版日期2011-7-15