Structure-based drug discovery for Dopamine D2 Receptor Selective Ligands

多巴胺 D2 受体选择性配体的基于结构的药物发现

• 批准号: 10212202
• 负责人: Victoria Ahn
• 金额: $ 73.81万
• 依托单位: CONFOMETRX, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212202
• 关键词: 3-Dimensional; Affect; Affinity; Agonist; Antipsychotic Agents; Applications Grants; Behavior; Binding; Brain; Centers for Disease Control and Prevention (U.S.); Central Nervous System Diseases; Clinical; Clinical Trials; Collaborations; Contracts; Custom; DNA; Development; Disease; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug Addiction; Functional disorder; Funding Opportunities; G-Protein-Coupled Receptors; Goals; Human; Lead; Libraries; Ligands; Maps; Medicine; Modeling; Nervous System Physiology; Neuraxis; Neurotransmitters; Parents; Parkinson Disease; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Phase; Process; Resolution; Rewards; Schizophrenia; Services; Small Business Innovation Research Grant; Structure; Substance Addiction; Substance abuse problem; United States National Institutes of Health; analog; base; density; design; drug discovery; drug of abuse; high throughput screening; improved; lead optimization; neurotransmission; nigrostriatal pathway; novel; novel lead compound; novel therapeutics; phase 1 study; preclinical study; receptor; response; screening; side effect; small molecule; small molecule libraries; substance abuse treatment; symptom treatment; therapeutic target; three dimensional structure; virtual screening

Summary The neurotransmitter dopamine (DA) controls many central nervous system functions through three major pathways in the brain, the tuberoinfundibular, the nigrostriatal and the mesocorticolimic (mesocortical and mesolimbic). Each is associated with different processes, and dysfunction can lead to varying diseases and disorders of the central nervous system (CNS). There are five known DA receptors, D2 (D2R) is one of the most abundant DA receptors in the brain, and is thus an important pharmacological target for many CNS diseases. Most of the clinically efficacious antipsychotics used for the treatment of schizophrenia and Parkinson's disease, which are associated with the mesocorticolimbic and nigrostriatal pathways, are D2R agonists or antagonists. However, new drugs with improved efficacy and side-effect profiles are needed for these relatively prevalent diseases. In addition, several drugs abused by humans affect DA neurotransmission in the mesolimbic pathway, due to their effects on reward-related behaviors. Therefore D2R is also a focus for the discovery of pharmacological treatments for substance abuse of a certain class of drugs and addiction disorders for which there are none currently available. The goal of this proposal is to discover novel D2R selective small molecule ligands that can be developed for the treatment of disorders of the CNS. Utilizing a combination of D2R three-dimensional structures, including the active-state structure obtained during our Phase I studies, virtual screening and DNA- encoded library screening, we will identify and develop novel lead compounds. These D2R targeted compounds will be optimized and undergo pre-clinical studies at which point we will seek commercial collaboration with a large pharmaceutical company. This proposal is in response to the Funding Opportunity Announcement PA-18- 574, “PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)”.

摘要 神经递质多巴胺(DA)控制许多中枢神经系统。 通过大脑中的三个主要途径发挥作用，即结节漏斗、 黑质纹状体和中皮质皮质(中皮质和中边缘)。每一个都是 与不同的过程相关，功能障碍会导致不同的 中枢神经系统(CNS)疾病和障碍。一共有五个 已知的DA受体D2(D2R)是体内含量最丰富的DA受体之一。 因此，它是许多中枢神经系统疾病的重要药理靶点。 大多数临床上有效的抗精神病药物用于治疗 精神分裂症和帕金森氏症，这与 中皮质边缘通路和黑质纹状体通路是D2R激动剂或拮抗剂。 然而，需要具有更好疗效和副作用的新药 对于这些相对流行的疾病。此外，几种药物被滥用 人类影响中脑边缘通路中的DA神经传递，因为他们的 对奖励相关行为的影响。因此，D2R也是 发现针对某类药物滥用的药物治疗方法 毒品和成瘾障碍，目前还没有可用的。这个 本方案的目标是发现新型的D2R选择性小分子配体 可以开发用于治疗中枢神经系统疾病的药物。利用一种 D2R三维结构的组合，包括有源态 我们在第一阶段研究中获得的结构，虚拟筛选和DNA- 通过对编码文库的筛选，我们将鉴定和开发新的先导化合物。 这些D2R靶向化合物将进行优化并进行临床前研究 研究，在这一点上，我们将寻求与大型 一家制药公司。 这项建议是对PA-18融资机会公告的回应- 574，“PHS 2018-02 NIH、CDC和FDA针对小型企业的综合征集 商业创新研究资助申请(家长SBIR[R43/R44] 不允许进行临床试验)“。