Three-Dimensional Pharmacophore Modeling of Liver-X Receptor Agonists
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文摘
High cholesterol levels contribute to hyperlipidemia. Liver X receptors (LXRs) are the drug targets. LXRs regulate the cholesterol absorption, biosynthesis, transportation, and metabolism. Novel agonists of LXR, especially LXR尾, are attractive solutions for treating hyperlipidemia. In order to discover novel LXR尾 agonists, a three-dimensional pharmacophore model was built based upon known LXR尾 agonists. The model was validated with a test set, a virtual screening experiment, and the FlexX docking approach. Results show that the model is capable of predicting a LXR尾 agonist activity. Ligand-based virtual screening results can be refined by cross-linking by structure-based approaches. This is because two ligands that are mapped in the same way to the same pharmacophore model may have significantly different binding behaviors in the receptor鈥檚 binding pocket. This paper reports our approach to identify reliable pharmacophore models through combining both ligand- and structure-based approaches.