Identification and elaboration of fluorine containing inhibitors of proline rich tyrosine kinase and endothelial nitric oxide synthase

富含脯氨酸酪氨酸激酶和内皮一氧化氮合酶的含氟抑制剂的鉴定和精制

• 批准号: 2743764
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2743764
• 关键词: Identification; elaboration; fluorine; containing; inhibitors

Type 2 Diabetes Mellitus, where our bodies do not produce enough insulin, or the insulin that is produced does not function properly,is an increasingly common disorder. Around four million people in the UK are affected by type 2 diabetes and it is estimated that 14 billion pounds is spent a year on treating diabetes and its complications in the UK alone. People with diabetes are up to five times more likely to have cardiovascular disease and their quality of life is likely to be more affected by it than people who don't have the disease.This is in part due to diabetes changing the cells that line your blood vessels, leading more toxic molecules in them and a decrease in beneficial molecules such as nitric oxide. We have recently shown that increased levels of a protein called PYK2 is found in the bodies of people with type 2 diabetes. This protein reduces nitric oxide levels by preventing the protein that makes nitric oxide (called eNOS) from working. We will use fragment based ligand discovery to identify fragments which modulate the interaction between eNOS and PYK2. These can be elaborated into small molecules. Fragment based ligand discovery allows greater sampling of chemical space compared with traditional screening techniques, even with a modestly sized compound library. Because of the weaker binding affinities typically exhibited by fragments, sensitive biophysical techniques such as Nuclear Magnetic Resonance are required to detect the binding event. The use of fluorine containing fragments for Nuclear Magnetic Resonance screening allows increased throughput versus fragments without a fluorine in as the spectra obtained are simplified and easier to read. This gives us the ability to screen mixtures of samples without spectral overlap, allowing cocktails of fragments, with around 10 compounds per tube, to be characterised, maximising efficiency.This newly discovered interaction offers a novel way to address the cardiovascular complications of type 2 diabetes. The new 4 channel Nuclear Magnetic Resonance probe at Leeds allows fluorine containing fragment screening for the first time. Results from this work will pave the way to develop therapies to treat type 2 diabetes targeting a previously unexploited pathway.

2型糖尿病，我们的身体不能产生足够的胰岛素，或者产生的胰岛素不能正常工作，是一种越来越常见的疾病。英国约有400万人患有2型糖尿病，据估计，仅在英国，每年就有140亿英镑用于治疗糖尿病及其并发症。糖尿病患者患心血管疾病的可能性是正常人的五倍，他们的生活质量可能比正常人受到更大的影响。这部分是由于糖尿病改变了血管细胞，导致更多的有毒分子进入血管，减少了有益分子，如一氧化氮。我们最近发现，在2型糖尿病患者体内发现一种名为PYK2的蛋白质水平增加。这种蛋白质通过阻止制造一氧化氮的蛋白质（称为eNOS）工作来降低一氧化氮水平。我们将使用基于片段的配体发现来鉴定调节eNOS和PYK2之间相互作用的片段。它们可以被加工成小分子。与传统的筛选技术相比，基于片段的配体发现允许更大的化学空间采样，即使是中等大小的化合物库。由于片段通常表现出较弱的结合亲和力，因此需要灵敏的生物物理技术如核磁共振来检测结合事件。使用含氟片段进行核磁共振筛选，与不含氟的片段相比，可以提高通量，因为获得的光谱简化且更容易读取。这使我们能够在没有光谱重叠的情况下筛选样品的混合物，允许每个试管中含有约10种化合物的碎片混合物进行表征，从而最大限度地提高效率。这种新发现的相互作用为解决2型糖尿病的心血管并发症提供了一种新方法。利兹新的4通道核磁共振探针首次允许含氟片段筛选。这项工作的结果将为开发治疗2型糖尿病的疗法铺平道路，该疗法针对以前未开发的途径。