Use of Bioinformatics and Genetics to Identify a New Class of Drugs for Neurological Disease

利用生物信息学和遗传学来鉴定一类治疗神经系统疾病的新药物

• 批准号: 10196360
• 负责人: SCOTT James MYERS
• 金额: $ 42.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196360
• 关键词: Alzheimer' s Disease; Binding; Binding Sites; Bioinformatics; Biological Markers; Cations; Cell physiology; Cells; Central Nervous System Diseases; Clinical; Codon Nucleotides; Cognition; Complex; Disease Progression; Drug Industry; Genetic; Genetic Variation; Glutamate Receptor; Glutamates; Glycine; Health; Human; Impaired cognition; In Vitro; Industry; Intellectual functioning disability; Investigation; Learning; Legal patent; Libraries; Ligands; Literature; Long-Term Potentiation; Mediating; Memory; Memory impairment; Methods; Modification; Mutagenesis; Mutation; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; Neurologic; Neurons; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Population; Probability; Process; Property; Quality of life; Role; Series; Site; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Therapeutic Intervention; Variant; analog; base; clinical development; cognitive ability; design; detector; developmental disease; experimental study; family burden; genetic analysis; ifenprodil; improved; in vivo; inhibitor/antagonist; innovation; insight; lead optimization; mutant; nervous system disorder; novel; novel drug class; novel therapeutics; patch clamp; positive allosteric modulator; pressure; programs; protein structure; receptor; receptor function; scaffold; screening; small molecule; virtual

NMDA receptors (NMDARs) can trigger synaptic plasticity due to their ability to act as coincident detectors of simultaneous neuronal firing and excitatory synaptic input, which can strengthen synapses by a cellular process known as long term potentiation (LTP). NMDARs play a critical role in cognition and memory formation, which is compromised in several neurological diseases. NMDARs are assemblies of two GluN1 subunits and two GluN2A-D subunits. Increased expression of GluN2B-containing NMDARs in vivo can enhance synaptic plasticity and memory, suggesting that GluN2B-selective positive allosteric modulators may facilitate learning. Finding ways to improve synaptic plasticity and memory formation could improve quality of life for patients with Alzheimer’s disease or intellectual disability. GluN2B-selective negative allosteric modulators (i.e. inhibitors) such as ifenprodil and analogues bind to the GluN1/GluN2B heterodimer amino terminal domain (ATD) interface. However, no drug-like GluN2B- selective positive allosteric modulator (i.e. potentiator) that binds to this site has been discovered despite the pharmaceutical industry screening many millions of compounds. Thus, if such modulators exist, they are absent from large screening libraries, which provide the starting point for virtually all medicinal chemistry efforts. In this proposal we exploit two advances in our understanding of NMDARs that could enable us to find new scaffolds for positive modulators. First, a crystallographic study of GluN2B-selective NMDAR inhibitors demonstrated a unique binding mode for the 93-series of Emory compounds, which occupy three branches of the triangular pocket located at the interface between the GluN1 and GluN2B ATDs. No other GluN2B- selective modulator binds in this fashion. We also discovered two GluN1 mutations near the modulator binding site that convert the action of Emory-synthesized GluN2B inhibitors, but not other classes of GluN2B inhibitors, into potentiators. This is the first evidence that a GluN2B-selective potentiator of NMDARs acting at the ifenprodil site can exist, and provides insight into what that molecule does to protein structure to make it a potentiator. We believe this insight together with structure-based design methods will support discovery of GluN2B potentiators of wild type NMDARs. Second, genetic variation in the healthy population has revealed that GluN1 and GluN2B residues in contact with ifenprodil have significantly fewer variants than expected, revealing that the ifenprodil binding pocket is under selective pressure. The only possible reasons for this are that these residues are critically important for receptor function, or an undiscovered endogenous modulator binds within this pocket and is important for health. We propose to test these two possibilities, including a screen of CSF for actions of a small molecule that binds within this pocket. We will carry out two sets of experiments: (1) design and synthesize GluN2B-selective positive allosteric modulators that act at the ifenprodil site, and (2) screen CSF for an endogenous modulator acting at the ifenprodil binding site.

NMDA受体（NMDAR）可以触发合成可塑性，因为它们的能力充当一致检测器 简单的神经元放电和兴奋性突触输入，可以通过细胞增强突触 过程称为长期增强（LTP）。 NMDAR在认知和记忆中起关键作用 形成，在几种神经系统疾病中受到损害。 NMDAR是两个Glun1的组件 亚基和两个glun2a-d亚基。在体内含有GLUN2B的NMDAR的表达增加可以 增强突触可塑性和记忆力，表明Glun2b选择性阳性变构调节剂可能 促进学习。寻找改善突触可塑性和记忆形成的方法可以提高 阿尔茨海默氏病或​​智力障碍患者的生活。 Glun2b选择性负变构调节剂（即抑制剂），例如Ifenprodil和类似物结合 Glun1/Glun2b异二聚体氨基终端域（ATD）界面。但是，没有类似药物的glun2b- 选择性阳性变构调节剂（即潜在的）与该站点结合的势态已被发现 制药行业筛查了数百万种化合物。如果存在这样的调节器，它们是 大型筛选文库缺乏，这为几乎所有药物化学提供了起点 努力。在此提案中，我们利用了对NMDAR的理解的两个进步，可以使我们能够找到 积极调节器的新脚手架。首先，Glun2b选择性NMDAR抑制剂的晶体学研究 展示了emory化合物的93系列的独特结合模式，该模式占据了三个分支 位于glun1和glun2b atds之间的界面上的三角袋。没有其他glun2b- 选择性调制器以这种方式绑定。我们还发现了调制器结合附近的两个Glun1突变 转换Emory合成的Glun2b抑制剂的作用，但没有其他类别的Glun2b 抑制剂，成为潜在剂。这是第一个证据表明，NMDAR的glun2b选择性潜在的作用 在Ifenprodil位置可以存在，并提供有关该分子对蛋白质结构做的事情的见解 它是一个潜在的人。我们认为，这种洞察力以及基于结构的设计方法将支持发现 野生型NMDAR的glun2b电势者其次，健康人群的遗传变异表明 Glun1和Glun2b与Ifenprodil保持接触的变化明显少于预期的， 表明ifenprodil结合口袋在选择性压力下。唯一可能的原因是 这些残留物对于受体功能至关重要，或未发现的内源调节剂 在这个口袋内绑定，对健康很重要。我们建议测试这两种可能性，包括 CSF的屏幕，用于在此口袋内结合的小分子的作用。我们将执行两套 实验：（1）设计和综合glun2b选择性的阳性变构调节剂 Ifenprodil位点和（2）屏幕CSF，用于作用于Ifenprodil结合位点的内源调节剂。