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

描述(由申请人提供)：肝X受体(LXRs)是核受体，其主要作用是维持胆固醇的稳态。众所周知，这些受体还在调节全身的脂肪和血糖水平方面发挥作用。LXRs已被证明是许多人类疾病的重要介体，包括动脉粥样硬化、糖尿病、心血管疾病、自身免疫性疾病、阿尔茨海默病和几种类型的癌症。重要的是，LXR激动剂已被证明对乳腺癌、前列腺癌和结直肠癌有很强的抗增殖作用，这些癌症是世界上最常见的癌症之一。LXR存在两种亚型，LXR�和LXR�LXR�S在肝脏中高表达，在肾脏、肠道、脂肪组织、肺、巨噬细胞和脾中也有表达，而LXR�S在全身普遍表达。LXRs在体内以不同的浓度存在，并在不同的组织中发挥不同的作用。已经观察到，非选择性激动剂降低血清胆固醇水平，并倾向于升高肝脏中的甘油三酯水平，这可能会导致严重的健康问题，而LXR�选择性激动剂往往在不影响甘油三酯水平的情况下降低胆固醇水平。因此，有强烈的动力开发选择性肝X受体调节剂(SLIMs)，其作用在不同组织中是不同的。在这里，我们建议进行的研究将导致新的特异性LXR激动剂的开发，选择性地结合LXR�。新的LXR异构体选择性配体的开发是我们朝着生产SLIMs迈出的一大步。事实上，识别或合成具有LXR异构体选择性的新配体本身就是一个重要的目标，并且可能在新药物的开发中具有至关重要的作用。将使用传统的分子对接和分子动力学(MD)方法、最先进的半经验量子力学评分函数(PM6-D3H4-SCORE)、化学合成和生物测定技术来研究配体与LXR�XR�结合的异构体选择性并开发新的LXR选择性配体。PM6-D3H4评分函数是一种创新的计算工具，从未在异构体选择性研究中使用过。中评分方法的准确性是至关重要的，因为与异构体选择性相关的结合自由能的差异通常很小。蛋白质-配体复合体是动态的，考虑分子运动是至关重要的。将进行MD模拟，以生成每个蛋白质-配体复合体的结构系综。配对分解和丙氨酸扫描将被用来确定导致配体效力和异构体选择性的最重要的相互作用。最先进的计算新药设计方法将被用来产生具有LXR�选择性的新药。结合效力和特异性将使用PM6-D3H4计分方法以及MD模拟方法进行测试。最有希望的新配体将被合成，并使用现代生物测定技术进行表征。

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.