The liver X receptor (LXR) is a ligand-activated protein that is responsible for regulation of cholesterol levels in the blood and cells. Manipulation of LXR binding activity has become a noteworthy subject of investigation because of its potential in the development of treatments for multiple diseases related to lipid and carbohydrate metabolism. Activation of LXRs results in reduction of cholesterol levels, which could be used as an effective regulator for diabetes or a potential method for starving cancer cells of necessary lipids. Using previously identified ligands that exhibited strong binding affinities to LXR, investigation of binding properties was conducted and further modifications were made to these ligands in an attempt to increase binding strength. Specific computational techniques that were used for this study were protein-ligand docking, methyl scanning, ethyl scanning, and scaffold replacement. To date, we have studied and developed methyl/ethyl derivatives for fourteen ligands that show promise of strong LXR binding activity. Currently, we are still in the process of further modifying these ligands using scaffold replacement. Once a maximum binding affinity is achieved, we hope to proceed in developing synthetic routes to synthesize the ligands. Once synthesized, the binding affinity of these ligands will be assessed using bioassay techniques.

Use of methyl scanning techniques in the development of novel ligands binding to the liver X receptor

255th National Meeting (2018)

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