Computationally informed discovery of scavenging-sparing inhibitors of CC chemokine receptor 2

通过计算发现 CC 趋化因子受体 2 的清除抑制剂

• 批准号: 10057631
• 负责人: Irina Kufareva
• 金额: $ 23.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-04 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057631
• 关键词: Agonist; Atherosclerosis; Autoimmune Diseases; Back; Behavior; Binding; Biological Assay; Biology; CC chemokine receptor 2; CCL2 gene; Cell surface; Chemicals; Clinic; Clinical; Complement; Complex; Coupled; Coupling; Disease; Environment; Failure; Fibrosis; Future; GTP-Binding Proteins; Goals; Hand; Human; In Vitro; Inflammation; Inflammatory; Investigation; Leukocytes; Libraries; Malignant Neoplasms; Measures; Mediating; Modeling; Molecular Conformation; Multiple Sclerosis; Myocardial Infarction; Outcome; Pathogenesis; Patients; Pharmacology; Plasma; Process; Proteins; Receptor Inhibition; Recycling; Rheumatoid Arthritis; Role; Safety; Sampling; Series; Side; Signal Transduction; Structure; Testing; Therapeutic; Tissues; Work; base; cell motility; chemical binding; chemokine; chemokine receptor; clinical candidate; clinical efficacy; conformational conversion; conformer; coronary fibrosis; design; follow-up; in silico; in vivo; inhibitor/antagonist; insight; macrophage; migration; molecular dynamics; monocyte; novel; painful neuropathy; prevent; receptor; receptor binding; receptor internalization; recruit; response; screening; side effect; small molecule; targeted agent; therapeutic target; three-dimensional modeling; tool; tumor-immune system interactions; virtual screening

The G protein-coupled CC chemokine receptor 2 (CCR2) is expressed on circulating monocytes and drives their recruitment to infected and damaged tissues, where the monocytes differentiate into infiltrating macrophages and promote the formation of an inflammatory pro-fibrotic environment. Because this process is key to the pathogenesis of many inflammatory diseases (rheumatoid arthritis, multiple sclerosis, neuropathic pain, and fibrosis, among others), CCR2 has been pursued for decades as a therapeutic target. However, no anti-CCR2 therapeutics have so far made it to the clinic, with most failing for lack of efficacy. Paradoxically, all known CCR2 antagonists cause a profound elevation in plasma levels of CCR2 agonist chemokine CCL2, which they were designed to inhibit in the first place. The therapeutic consequences of this are not clear: the elevation may be a desired (via blunting of chemokine gradients and migratory responses) or an unwanted (via “inhibition of an inhibitor”) phenomenon. Additional complexity arises from non-migratory functions of CCL2 in e.g. regulating leukocyte differentiation. Concerningly, antagonist-induced CCL2 elevation reaches its peak when the plasma concentration of the antagonist itself wanes. Therefore, this side effect may compromise the safety and efficacy of anti-CCR2 clinical candidates. Unfortunately, systematic investigation of this phenomenon in vivo is currently impossible, for the lack of proper pharmacological tools. The applicants’ long-term goal is to decipher the intricacies of CCR2 signaling and to develop clinically successful CCR2-targeting agents. The applicants have recently discovered the basis for antagonist-induced CCL2 elevation, and demonstrated that it occurs via inhibition of an important but underappreciated regulatory function of CCR2 where it scavenges CCL2 constitutively produced by tissues, and clears it from plasma. Scavenging is inhibited because all known antagonists prevent chemokine binding to CCR2. These findings outline the conceptual possibility of an antagonist of CCR2-mediated migration that does not cause CCL2 elevation, by sparing chemokine binding to CCR2 and hence its scavenging. The goal of the present proposal is to discover such antagonists via a computationally guided approach, by pursuing two Specific Aims: (1) Via in silico compound library screening against an ensemble of CCR2:CCL2 complex models, identify chemicals that bind CCR2 concurrently with CCL2, and characterize their pharmacology in vitro. (2) Computationally elucidate the dynamics of CCR2 in complex with CCL2, and identify G-protein- incompatible states with the potential to enrich for scavenging-sparing inhibitors in VLS. The outcome of the proposed work will be the discovery of the first chemical probes with novel pharmacology in relation to CCR2: the inhibitors of CCR2-mediated cell migration that spare CCL2 scavenging. These molecules will assist investigations of antagonist-induced CCL2 elevation in vivo by the applicant’s group and others. The findings will also inform future efforts of therapeutic targeting of CCR2 for inflammation and cancer.

G蛋白偶联的CC趋化因子受体2（CCR2）在循环单核细胞上表达并驱动其 招募受感染和受损的组织，单核细胞分化为浸润的巨噬细胞 并促进炎症性纤维化环境的形成。因为此过程是 许多炎症性疾病（类风湿关节炎，多发性硬化症，神经性疼痛和 纤维化，等等）CCR2已被追捕数十年来是治疗靶标。但是，没有抗CCR2 到目前为止，治疗药已经到了诊所，由于缺乏效率，最大的疗法。 矛盾的是，所有已知的CCR2拮抗剂在CCR2激动剂的等离子体水平上升高 趋化因子CCL2首先设计为抑制。理论的后果 不清楚：海拔可能是理想的（通过趋化因子梯度和迁移反应的钝化）或 不需要的（通过抑制剂的抑制作用”）现象。非移民产生了额外的复杂性 CCL2在例如调节白细胞分化。关于拮抗剂诱导的CCL2高程 当拮抗剂本身的血浆浓度减弱时，达到峰值。因此，这种副作用可能 损害了抗CCR2临床候选物的安全性和有效性。不幸的是，系统调查 由于缺乏适当的药物工具，目前在体内这种现象是不可能的。 申请人的长期目标是破译CCR2信号的复杂性并发展临床成功 CCR2靶向代理。申请人最近发现了拮抗剂诱导的CCL2的基础 高程，并证明它通过抑制重要但不足的调节功能而发生 CCR2的ccr2清除CCL2由组织组成性产生，并将其从等离子体中清除。清除是 抑制是因为所有已知的拮抗剂都可以防止趋化因子与CCR2结合。这些发现概述了 CCR2介导的迁移的拮抗剂的概念可能性不会导致CCL2高程 保留趋化因子与CCR2的结合，从而清除。本提议的目的是发现 通过计算指导的方法，通过追求两个具体目标：（1）通过计算机： CCR2合奏：CCL2复合模型的复合库筛选，识别化学物质 该CCR2与CCL2同时结合，并在体外表征其药理学。 （2） 在计算中阐明与CCL2复合物中CCR2的动力学，并识别G蛋白 不兼容的状态有可能富集VLS中的抑制剂。 拟议工作的结果将是发现新型药理学的第一个化学问题 与CCR2的关系：CCR2介导的细胞迁移的抑制剂，使CCL2清除。这些分子 将协助申请人组和其他人在体内对拮抗剂引起的CCL2高程的投资。 调查结果还将为CCR2治疗靶向注射和癌症的未来努力。