A combination of pharmacophore modeling, molecular docking and virtual screening for NPC1L1 receptor inhibitors from Chinese herbs

NPC1L1, a protein localized in jejunal enterocytes, is critical for cholesterol absorption. As the receptor inhibitors are effective solutions for hyperlipidaemia, NPC1L1 receptor is becoming a hot spot in drug targets. In this study, pharmacophore modeling and molecular docking were combined to discover potential NPC1L1 inhibitors from traditional Chinese medicine. The best pharmacophore model, Hypo1, which was generated by 9 known inhibitors, comprised of two Hydrogen bond acceptor lipid and two Hydrophobic aromatic regions. And the active compounds hit rate (A%), identification index (N), and comprehensive evaluation index (CAI) are 100%, 3.852, and 3.852 respectively. Hypo1 was used to screen TCMD (version 2009) to identify potential inhibitors, which resulted in a hit list of 38 compounds with Lipinski´s rule of five. In addition, docking was used to refine pharmacophore-based screening results by using ezetimibe as a reference. Then, 11 compounds with higher docking score than ezetimibe had been reserved. This paper provides a reliable utility for discovering natural NPC1L1 receptor inhibitors from traditional Chinese herbs.