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）：肝脏X受体（LXRs）是核受体，其主要作用是在胆固醇稳态中。这些受体也被认为在调节全身脂质和葡萄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质，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激动剂已被证明在乳腺癌、前列腺癌和结直肠癌中具有很强的抗增殖作用，这是世界上最常见的癌症形式之一。LXR存在两种异构体：LXR和LXR， LXR在肝脏中高表达，也存在于肾脏、肠道、脂肪组织、肺、巨噬细胞和脾脏中，而LXR在全身普遍表达。lxr在全身的浓度不同，在不同的组织中起着不同的作用。据观察，非选择性激动剂降低血清胆固醇水平，也倾向于提高肝脏中的甘油三酯水平，这可能导致严重的医疗问题，而LXR选择性激动剂倾向于降低胆固醇水平而不影响甘油三酯水平。因此，有强烈的动力开发选择性肝脏X受体调节剂（SLiMs），其作用在不同组织中是不同的。在这里，我们建议开展研究，以开发新的选择性结合LXR的异构体特异性LXR激动剂。新的LXR异构体选择性配体的开发代表了我们在slms生产方面的一大步。事实上，鉴定或合成具有LXR异构体选择性的新配体本身就是一个重要的目标，并且可能对新药的开发具有至关重要的意义。将利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结合的异构体选择性和开发新的LXR选择性配体。PM6-D3H4-Score评分功能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。评分方法的准确性是至关重要的，因为与同工异构体选择性相关的结合自由能的差异通常很小。蛋白质配体复合物是动态的，考虑分子运动是至关重要的。MD模拟将用于生成每个蛋白质配体复合物的结构集成。两两分解和丙氨酸扫描将用于确定最重要的相互作用，导致配体的效力和异构体的选择性。最先进的计算新生药物设计方法将用于产生具有LXR选择性的新药物。结合效力和特异性将使用PM6-D3H4-Score方法和MD模拟方法进行测试。最有前途的新配体将使用现代生物测定技术进行合成和表征。

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.