Small Molecule Probes to Investigate Structure and Function of Y Receptors

研究 Y 受体结构和功能的小分子探针

基本信息

批准号：
8890156
负责人：
Jens Meiler
金额：
$ 33.95万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8890156
关键词：
Adverse effects Affinity Agonist Amino Acids Animals Arrestins Binding Binding Sites Biochemistry Biological Availability Biological Neural Networks Biology Brain Stem COS Cells Cell Line Chemicals Chemistry Chemosensitization Cluster Analysis Collaborations Computing Methodologies Cone Consultations Coupling Data Development Docking Electrophysiology (science)Family Feeding behaviors Future G-Protein-Coupled Receptors Health Histamine Receptor Homeostasis Human In Vitro Institutes Label Libraries Ligand Binding Ligands Machine Learning Metabolic Diseases Modeling Molecular Bank Obesity Pancreas Pancreatic Polypeptide Peptides Peripheral Pharmacology Phase II Clinical Trials Play Quantitative Structure-Activity Relationship Role Seeds Signal Pathway Site Source Structure Testing Therapeutic Tissues Universities Variant Work base brain tissue chemical synthesis cheminformatics design drug discovery experience high throughput screening interest member neuropeptide Y neuropeptide Y4 receptor novel obesity treatment peptide hormone polypeptide programs receptor research study response screening small molecule therapeutic development tissue-factor-pathway inhibitor 2 treatment strategy virtual

项目摘要

DESCRIPTION (provided by applicant): The neuropeptide Y4 receptor (Y4) is a 375 amino acid G-protein coupled receptor (GPCR) that is ex- pressed mainly in peripheral tissues and the brain stem. In humans, Y4 belongs to a family of receptors (Y1, Y2, Y4, and Y5), that bind the ligands neuropeptide Y (NPY), polypeptide YY (PYY) and pancreatic polypeptide (PP). NPY, PYY and PP are 36 residue peptide hormones that play critical roles in regulating feeding behavior and energy homeostasis. Y4 is the only receptor subtype with low affinity for NPY and PYY and very high (picomolar) affinity for PP5. Thus, selective agonists of Y4 could be promising candidates for obesity therapeutics. In fact Obinepitide (TM-30338), a variant of PP and PYY, is currently in phase II clinical trials as a treatment for obesity. However as Obinepitide is a peptide, issues of stability and bioavailability remain. Development of non-peptidic Y4-selective ligands that bind to the endogenous binding site have failed so far. The objective of the present proposal is to identify small molecule allosteric modulators of the Y4 receptor. Allosteric modulators of GPCRs have a higher chance to be selective as allosteric binding sites tend to be evolutionary less conserved between receptor subtypes. The therapeutic potential of allosteric modulators is further increased by their ability to tune the receptor response instead of simply turning it on or off. Side effects may also be reduced for allosteric potentiators because the therapeutic only acts when the receptor is engaged by its native ligand. In preliminary work, we have adapted a Y4 functional assay for high-throughput screening (HTS) experiments that can detect agonists, antagonists and allosteric modulators simultaneously. We con- ducted a pilot screen of 2,000 compounds that yielded several hits including one, Niclosamide that displayed robust, selective allosteric potentiation with an EC50~400 nM. The proposed experiments will be used in combination with computational methods that enable virtual screening of millions of compounds. We will construct quantitative structure activity relationship (QSAR) models to create libraries focused around initial hit compounds and libraries enriched with novel chemotypes predicted to be Y4 allosteric modulators. Identification of small molecule allosteric modulators of Y4 will allow future development of pharmacological probes and can seed drug discovery programs in obesity.

描述（申请人提供）：神经肽Y4受体（Y4）是一种375个氨基酸的G蛋白偶联受体（GPCR），主要在外周组织和脑干中表达。在人类中，Y4 属于受体家族（Y1、Y2、Y4 和 Y5），可结合配体神经肽 Y (NPY)、多肽 YY (PYY) 和胰多肽 (PP)。 NPY、PYY 和 PP 是 36 残基肽激素，在调节摄食行为和能量稳态方面发挥着关键作用。 Y4 是唯一对 NPY 和 PYY 具有低亲和力而对 PP5 具有非常高（皮摩尔）亲和力的受体亚型。因此，Y4 的选择性激动剂可能是肥胖治疗的有希望的候选者。事实上，Obinepitide (TM-30338) 是 PP 和 PYY 的变体，目前正处于治疗肥胖症的 II 期临床试验中。然而，由于奥宾肽是一种肽，因此稳定性和生物利用度问题仍然存在。迄今为止，与内源结合位点结合的非肽 Y4 选择性配体的开发尚未成功。本提案的目的是鉴定 Y4 受体的小分子变构调节剂。 GPCR 的变构调节剂具有更高的选择性机会，因为受体亚型之间的变构结合位点往往在进化上不太保守。变构调节剂的治疗潜力通过其调节受体反应而不是简单地打开或关闭它的能力而进一步增加。变构增强剂的副作用也可以减少，因为治疗剂仅在受体与其天然配体结合时才起作用。在前期工作中，我们采用了 Y4 功能测定法进行高通量筛选 (HTS) 实验，可以同时检测激动剂、拮抗剂和变构调节剂。我们对 2,000 种化合物进行了初步筛选，产生了多种化合物，其中包括一种氯硝柳胺，它显示出强大的选择性变构增强作用，EC50~400 nM。所提出的实验将与计算方法结合使用，从而能够虚拟筛选数百万种化合物。我们将构建定量结构活性关系 (QSAR) 模型，以创建专注于初始命中化合物的库和富含预计为 Y4 变构调节剂的新型化学型的库。 Y4 小分子变构调节剂的鉴定将有助于未来药理学探针的开发，并可为肥胖症药物发现计划奠定基础。