The liver X receptor (LXR) a nuclear receptor whose main function is regulation of cholesterol levels in cells and in the blood. In recent years it has been recognized that LXR may serve as an excellent pharmaceutical target for hypercholesterolemia and potentially in the treatment of cancer (breast, prostate, colon). The targeting of LXR for cancer is based on the idea of starving cancer cells of cholesterol. To date, several LXR agonists and antagonists have been developed and tested on animal models. Unfortunately, many of these synthetic ligands have shown adverse side effects (often involving the central nervous system). Here we carry out computational studies to develop novel LXR ligands that, ideally, will not exhibit strong side effects, rendering them inefficacious. Our computational studies are mainly focused on the use of scaffold replacement techniques to develop novel ligands that bind strongly to LXR. Methyl scanning techniques, in which methyl groups are used to fill critical areas within the protein binding pocket, are used to improve binding scores with great success. Several ligands with strong binding properties have been synthesized in the laboratory and their activities have been tested using bioassay techniques.

Design and synthesis of novel liver X receptor ligands

253rd National Meeting (2017)

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