Structural Approaches for Understanding Opioid and ??-Receptor Interactions

理解阿片类药物和 β-受体相互作用的结构方法

• 批准号: 8288784
• 负责人: Renyu Liu
• 金额: $ 12.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288784
• 关键词: Address; Adrenergic Receptor; Adverse effects; Affinity; Agonist; Algorithms; Analgesics; Anesthesia procedures; Area; Binding; Binding Sites; Biochemical; Biological Assay; Cattle; Cessation of life; China; Circular Dichroism; Client satisfaction; Clinical; Commit; Constipation; Crystallization; Crystallography; Data; Detergents; Docking; Economics; Engineering; Escherichia coli; Faculty; Fentanyl; Goals; Homology Modeling; Human; Investigation; Japan; Ligands; Medicine; Mentors; Methods; Modeling; Morbidity - disease rate; Morphine; Mutation; Naloxone; Opiates; Opioid; Opioid Analgesics; Opioid Receptor; Pain management; Patient Care; Patients; Perioperative; Pharmaceutical Preparations; Physicians; Property; Protein Engineering; Proteins; Public Health; Publishing; Records; Relative (related person); Resolution; Resources; Rhodopsin; Scientist; Site; Solubility; Solutions; Structural Models; Structure; System; Testing; Training; United States; Variant; Ventilatory Depression; Water; addiction; career; chronic pain; design; improved; light scattering; molecular dynamics; molecular recognition; mortality; mu opioid receptors; novel; public health relevance; receptor; skills; water environment

DESCRIPTION (provided by applicant): Opioids remain the major medication for perioperative and chronic pain management, but their side effects, which include respiratory depression, constipation, addiction and others, relate to morbidity and mortality in our patients, as well as presenting a significant economic and political burden. Since both the analgesic and side effects are thought to arise from activation of the mu receptor (MUR), a better understanding of the structural and functional relationships of human MUR might provide clues for addressing this clinical dilemma. My long-term goal is to reveal the molecular recognition mechanism of opiates and opiate receptors by using biochemical, biophysical, protein engineering and the high resolution structural approaches. In this project, 4 specific aims are proposed. In aim 1, we will establish a novel structural model of the human MUR from a combination of rhodopsin structural data and the newly available experimental structures of human ?2 adrenergic receptor. This will permit opioid and MUR interaction studies at the computational level. In aim 2, we will engineer a variant of the water soluble, but structurally unaltered water soluble mu receptor (WSMUR) for dynamic opioid and receptor interactions in solution conditions. In aim 3, we will express the WSMUR for biophysical characterization studies and for various binding studies with opioids in solution conditions. In aim 4, we will crystallize the WSMUR for structural determinations in the presence or absence of opioids. As an anesthesiologist, formerly trained in academic centers in China, Japan, and United States, Dr. Liu is firmly committed to a career in academic anesthesia. His ultimate career goal is to achieve a better understanding of opioid and opioid receptor interactions, and use these data to develop optimal analgesics to ultimately improve patient care and satisfaction. This proposal will help him to reach his goals by providing further training and resources. His co-mentors have established records of nurturing junior faculty. Together with his current skill set, the advanced training enabled through the K-08 will help transition Dr. Liu towards an independent physician scientist in the area of perioperative medicine. PUBLIC HEALTH RELEVANCE: This project uses alternative structural approaches to investigate the relationship between opioids and human mu receptor. The information derived from this project may help to design novel opioid analgesics with minimal side effects, improve pain control, and solve issues related to opioids administration and abuse. Thus, this project has significant implications for public health.

描述（由申请人提供）：阿片类药物仍然是围手术期和慢性疼痛管理的主要药物，但是它们的副作用，包括呼吸抑郁，便秘，成瘾等，与患者的发病率和死亡率有关，并表现出巨大的经济和政治负担。由于镇痛和副作用都被认为是由MU受体（MUR）的激活引起的，因此对人MUR的结构和功能关系的更好理解可能为解决这一临床困境提供了线索。我的长期目标是通过使用生化，生物物理，蛋白质工程和高分辨率结构方法来揭示阿片类药物和阿片受体的分子识别机制。在该项目中，提出了4个具体目标。在AIM 1中，我们将通过视紫红质结构数据和人类2肾上腺素能受体的新可用实验结构的结合来建立人类MUR的新结构模型。这将允许在计算水平上进行阿片类药物和MUR相互作用研究。在AIM 2中，我们将设计水溶性的变体，但结构不变的水溶性MU受体（WSMUR）在溶液条件下进行动态阿片类药物和受体相互作用。在AIM 3中，我们将表达生物物理表征研究的WSMUR和在溶液条件下使用阿片类药物的各种结合研究的WSMUR。在AIM 4中，我们将在存在或不存在阿片类药物的情况下将WSMUR结晶以进行结构测定。作为一名麻醉师，以前在中国，日本和美国接受过学术中心培训，刘博士坚定地致力于学术麻醉的职业。他的最终职业目标是更好地了解阿片类药物和阿片类药物的相互作用，并使用这些数据来开发最佳的镇痛药，以最终提高患者护理和满意度。该提议将通过提供进一步的培训和资源来帮助他实现目标。他的副官员已经建立了培养初级教师的记录。通过当前的技能，通过K-08进行了高级培训，将有助于刘博士向围手术医学领域的独立医师科学家过渡。 公共卫生相关性：该项目使用替代性结构方法来研究阿片类药物与人类MU受体之间的关系。从该项目获得的信息可能有助于设计新颖的阿片类镇痛药，具有最小的副作用，改善疼痛控制，并解决与阿片类药物给药和滥用有关的问题。因此，该项目对公共卫生具有重要意义。