Discovery of natural products for dual pharmacology CETP inhibitors and niacin receptor agonists

Dyslipidemia is a leading causative factor in cardiovascular diseases, and the traditional modulating lipid drugs mainly focus on reducing Low Density Lipoprotein Cholesterol (LDL-C). However, the increase of High Density Lipoprotein Cholesterol (HDL-C) also has gradually become an important focus on modulating lipid drugs. It is universally acknowledged that the drugs for significantly increasing HDL-C act on either the niacin receptor or cholesteryl ester transfer protein (CETP). Therefore, by comprehensively considering advantages and shortness of these two drug targets, compounds which act on the dual targets were studied in this paper. To be specific, a HipHop pharmacophore model for CETP inhibitors was built firstly, and then the pharmacophore model was validated internally and externally. The best pharmacophore model for CETP inhibitors included one hydrogen bond acceptor, four hydrophobic groups and two ring aromatics. In addition, the common basic structure of niacin receptor agonists was analyzed, and the novel basic structure was designed by bioisosterism principle. Afterward, the database of niacin receptor agonists, including 214 compounds, was established by fragment searching from traditional Chinese medicine database (TCMD, version 2009) and Lipinski' rules. Finally, five natural products with dual targets activity were gained by using CETP inhibitors pharmacophore model to screen the molecular database of niacin receptor agonists, which provided the study of dual-targets drug design with a reliable utility.