Generation of Liver X Receptor Agonists with LXRb Subtype Selectivity using Modern Computational and Chemical Synthetic Methods

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DESCRIPTION (provided by applicant): The liver X receptors (LXRs) are nuclear receptors whose primary role is in cholesterol homeostasis. These receptors are also known to play roles in the regulation of lipid and glucose levels throughout the body. The LXRs 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. Importantly, LXR agonists have been shown to have strong antiproliferative effects in breast, prostate, and colorectal cancers, which are among the most common forms of cancer worldwide. LXRs exist in two isoforms, LXR�nd LXR�LXR�s highly expressed in liver and is also present in kidneys, intestine, adipose tissue, lungs, macrophages, and spleen while LXR�s ubiquitously expressed throughout the body. The LXRs are present in varying concentrations throughout the body and play different roles in different tissues. 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 LXR�elective 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 propose to conduct research that will lead to the development of new isoform-specific LXR agonists that selectively bind LXR�The development of new LXR isoform-selective ligands represents a large step in our progress toward production of SLiMs. Indeed, identification or synthesis of new ligands with LXR isoform selectivity is an important goal in itself, and may have critical importance in the development of new pharmaceuticals. Isoform selectivity of ligands binding to LXR�XR�nd develop new LXRselective ligands will be investigated using traditional molecular docking and molecular dynamics (MD) methods, a state-of-the-art semiempirical quantum mechanical scoring function (PM6-D3H4-Score), chemical synthesis, and bioassay techniques. The PM6-D3H4-Score scoring function is an innovative computational tool that has never been utilized in isoform selectivity studies. The accuracy of the scoring method in is critical, as the differences in bindig free energies associated with isoform selectivity are generally small. Protein-ligand complexes are dynamic and it is critical to take molecular motion into account. MD simulations will be carried out to generate structural ensembles for each protein-ligand complex. Pairwise decomposition and alanine scanning will be used to determine the most important interactions leading to ligand potency and isoform selectivity. State-of-the-art computational de novo drug design methods will be used to generate novel drugs that exhibit LXR�electivity. Binding potency and specificity will be tested using the PM6-D3H4-Score method as well as MD simulation methods. The most promising of the new ligands will be synthesized and characterized using modern bioassay techniques.