Development of Opioid Receptor Models for Rational Design of Bifunctional Ligands

开发阿片受体模型以合理设计双功能配体

• 批准号: 7512750
• 负责人: Judith Varady Hobrath
• 金额: $ 27.26万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7512750
• 关键词: Absence of pain sensation; Adverse effects; Affinity; Agonist; Analgesics; Attenuated; Binding; Binding Sites; Characteristics; Class; Clinical Treatment; Complex; Computer Simulation; Condition; Coupled; Dependence; Development; Drug Design; G-Protein-Coupled Receptors; Generations; Genes; Goals; Health; Individual; Knock-out; Knowledge; Ligand Binding; Ligands; Mediating; Medical; Methods; Modeling; Morphine; Numbers; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Performance; Personal Satisfaction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Property; Public Health; Research; Resources; Sampling; Series; Structural Models; Structure; Testing; Therapeutic Agents; addiction; analog; base; chronic pain; delta opioid receptor; design; expectation; improved; insight; knowledge base; mu opioid receptors; next generation; novel; novel strategies; novel therapeutics; pharmacophore; phenylmorphan; prevent; receptor; receptor binding; scaffold; three-dimensional modeling

DESCRIPTION (provided by applicant): Opioids still remain the primary drugs for the treatment of moderate to severe pain. The analgesic effects of currently available opioid drugs are mediated through their agonist interaction with the mu opioid receptor. The use of these mu agonist opioid analgesics is severely restricted by a number of serious side effects such as development of tolerance and dependence and the potential for addiction. Recent research using opioid receptor subtype selective antagonist and agonist ligands as well as gene knock out studies have provided convincing evidence that the blockade of opioid delta receptors can diminish or prevent the side effects of mu agonist analgesics without diminishing their analgesic effects. This has provided an impetus for discovering novel nonpeptide opioid ligands possessing mixed mu agonist/delta antagonist activity since ligands endowed with such a profile have the potential of emerging as new therapeutic agents for alleviating pain without attendant tolerance and dependence side effects. Current medicinal chemistry research focusing on the design of such mixed function ligands primarily depend on ligand structure based approaches. These drug design efforts could gain a significant advantage if requirements of potent agonist and antagonist binding are delineated through development of structural models of the mu and delta receptor in the active and inactive states. The availability of increasing computational resources coupled with advances in computational modeling of G-protein coupled receptors (GPCRs) allows further exploration of the structural basis of ligand binding and activation of the opioid receptors and their heterooligomers and the rational design of new generation of opioid analgesics. To achieve these long-term goals, proposed herein is a research effort focusing on the following specific aims: (1) Develop a three dimensional models of the mu opioid receptor in the active state and delta opioid receptor in the inactive state and refine these models using enhanced conformational sampling methods (2) Develop pharmacophores for ligand binding and activation at mu receptors and binding and antagonist activity at delta receptors through structure predictions from ligand- receptor complexes (3) On the basis of the knowledge gained, design, synthesize, and evaluate new ligands with improved binding and activity profiles and refine and evaluate models on the basis of experimentally determined activity profiles and (4) Explore modeling the structures of mu-delta heterodimer complexes to gain insight into novel binding site characteristics that such interactions confer to these complexes. The proposed research therefore should enhance our fundamental knowledge and understanding of the interaction of various ligands with these receptors in addition to enhancing the prospect of designing and developing new improved ligands with the potential for emerging as potent analgesic drugs for pain relief devoid of severe side effects. PUBLIC HEALTH RELEVANCE: Severe and chronic pain is a debilitating medical condition that has a huge impact on the health and well-being of a large number of individuals. Although opioid drugs are potent pain relievers, their general use is severely restricted by side effects such as tolerance and dependence. The proposed research is focused on computational modeling of the opioid receptors to enable the design and discovery of new, potent opioid analgesic compounds devoid of the limiting side effects associated with the current medications.

描述（由申请人提供）：阿片类药物仍然是治疗中度至重度疼痛的主要药物。目前可用的阿片类药物的镇痛作用是通过其激动剂与μ阿片受体的相互作用来介导的。这些μ激动剂阿片类镇痛药的使用受到许多严重副作用的严重限制，例如产生耐受性和依赖性以及成瘾的可能性。最近使用阿片受体亚型选择性拮抗剂和激动剂配体以及基因敲除研究提供了令人信服的证据，表明阻断阿片δ受体可以减少或预防μ激动剂镇痛药的副作用，而不减弱其镇痛作用。这为发现具有混合μ激动剂/δ拮抗剂活性的新型非肽阿片类配体提供了动力，因为具有这种特征的配体有可能成为减轻疼痛的新治疗剂，而不会伴随耐受性和依赖性副作用。当前专注于此类混合功能配体设计的药物化学研究主要依赖于基于配体结构的方法。如果通过开发处于活性和非活性状态的 mu 和 delta 受体的结构模型来描述有效激动剂和拮抗剂结合的要求，这些药物设计工作可以获得显着的优势。计算资源的增加加上 G 蛋白偶联受体 (GPCR) 计算模型的进步，可以进一步探索阿片受体及其异低聚物的配体结合和激活的结构基础，以及新一代阿片类镇痛药的合理设计。为了实现这些长期目标，本文提出的研究工作重点关注以下具体目标：（1）开发活性状态μ阿片受体和非活性状态δ阿片受体的三维模型并完善这些模型使用增强的构象采样方法 (2) 通过配体-受体复合物的结构预测，开发用于 mu 受体的配体结合和激活以及 delta 受体的结合和拮抗剂活性的药效团 (3) 根据所获得的知识，设计、合成和评估具有改进的结合和活性特征的新配体，并在实验确定的活性特征的基础上完善和评估模型，以及（4）探索 mu-delta 异二聚体复合物结构的建模，以深入了解此类相互作用的新结合位点特征赋予这些复合体。因此，拟议的研究除了增强设计和开发新的改进配体的前景之外，还应增强我们对各种配体与这些受体相互作用的基础知识和理解，这些配体有可能成为有效的镇痛药物，用于缓解疼痛，且没有严重的副作用。公共健康相关性：严重和慢性疼痛是一种使人衰弱的疾病，对许多人的健康和福祉产生巨大影响。尽管阿片类药物是有效的止痛药，但其普遍使用受到耐受性和依赖性等副作用的严重限制。拟议的研究重点是阿片受体的计算模型，以便设计和发现新的、有效的阿片类镇痛化合物，避免与当前药物相关的限制性副作用。