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（由申请人提供）：神经肽Y4受体（Y4）是375个氨基酸G蛋白偶联受体（GPCR），主要是在外周组织和脑干中进行的。在人类中，Y4属于结合配体神经肽Y（NPY），多肽YY（PYY）和胰腺多肽（PP）的受体家族（Y1，Y2，Y4和Y5）。 NPY，PYY和PP是36个残基肽激素，在调节喂养行为和能量稳态中起着关键作用。 Y4是唯一对NPY和PYY的亲和力低的受体亚型，并且对PP5非常高（皮摩尔）的亲和力。因此，Y4的选择性激动剂可能是肥胖治疗的有前途的候选者。实际上，PP和PYY的一种变体Obinepitide（TM-30338）目前正在II期临床试验中作为肥胖症治疗。但是，由于obinepitide是一种肽，因此仍然存在稳定性和生物利用度的问题。到目前为止，与内源性结合位点结合的非肽Y4选择配体的发展已经失败。本提案的目的是确定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，因为变构结合位点在受体亚型之间往往是进化较少的保守性。变构调节剂的治疗潜力通过调整受体反应而不是简单地打开或关闭的能力进一步提高。变构增强剂也可能会降低副作用，因为治疗仅在受体与天然配体接合时起作用。在初步工作中，我们对Y4功能测定法进行了高通量筛选（HTS）实验，该实验可以同时检测激动剂，拮抗剂和变构调节剂。我们配备了2,000种化合物的试验屏幕，该屏幕产生了几次命中，其中包括一种烟酰胺，显示出强大的，具有EC50〜400 nm的选择性变构增强。所提出的实验将与计算方法结合使用，该方法能够虚拟筛选数百万种化合物。我们将构建定量结构活动关系（QSAR）模型，以创建围绕初始命中化合物和库的库，这些化合物和库富含预测为Y4变构调节剂的新型化学型。鉴定Y4的小分子变构调节剂将允许将来开发药理学探针，并可以在肥胖症中播种药物发现程序。