aShionogi Research Laboratories, Shionogi & Company, Ltd, Sagisu, Fukushima-ku, Osaka 553-0002, Japan
bShionogi Research Laboratories, Shionogi & Company, Ltd, Mishima, Settsu-shi, Osaka 556-0022, Japan
Abstract:
We propose a two-metal binding model as a potential mechanism of chelating inhibitors against HIV integrase (HIV IN) represented by 2-hydroxy-3-heteroaryl acrylic acids (HHAAs). Potential inhibitors would bind to two metal ions in the active site of HIV IN to prevent human DNA from undergoing the integration reaction. Correlation of the results of metal (Mg2+ and Mn2+) titration studies with HIV IN inhibition for a series of active and inactive compounds provides support for the model. Results suggest Mg2+ is an essential cofactor for chelating inhibitors.