The LXRs are a nuclears receptor, exhibiting two isoforms (LXRα and LXRβ), that have been demonstrated to be important mediators in a number of human diseases, including atherosclerosis, diabetes, cardiovascular disease, autoimmune disorders, Alzheimer’s disease, and several types of cancer. It has been observed that nonselective agonists lower serum cholesterol levels and also tend to raise triglyceride levels in the liver, which can lead to serious medical issues, while LXRβ-selective agonists tend to lower cholesterol levels without affecting triglyceride levels; thus, there is a strong drive to develop selective liver X receptor modulators (SLiMs) whose action is different in various tissues. Here we use computational chemistry methods to investigate the binding of four ligands, 2 α-selective, 1 β-selective, and one non-selective, to both LXRα and LXRβ. Molecular dynamics techniques are used to generate an ensemble of protein-ligand structures for each of the systems and protein-ligand scoring methods are used to generate estimates of binding free energies. Glycin scanning methods are used to investigate the particular ligand-residue contacts that are responsible for ligand binding and LXRα/β selectivity.

Computational investigations on ligand isoform selectivity in the liver X receptors

249th National Meeting (2015)

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