Development of Opioid Receptor Models for Rational Design of Bifunctional Ligands

描述(申请人提供)：阿片类药物仍然是治疗中度到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它们与Mu阿片受体的激动剂相互作用来实现的。这些MU激动剂阿片类镇痛剂的使用受到一些严重副作用的严重限制，例如形成耐受性和依赖性以及可能上瘾。最近使用阿片受体亚型选择性拮抗剂和激动剂配体的研究以及基因敲除研究提供了令人信服的证据，表明阻断阿片受体可以在不削弱MU激动剂止痛药的副作用的情况下减少或防止其副作用。这为发现具有MU激动剂/Delta拮抗剂混合活性的新型非肽类阿片配体提供了动力，因为具有这种特性的配体有可能成为新的止痛药物，而不伴随耐受和依赖副作用。目前的药物化学研究主要集中在设计这种混合功能配体上，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对有效的激动剂和拮抗剂结合的需求，这些药物设计工作将获得显著的优势。随着计算资源的增加和G蛋白偶联受体(GPCRs)计算模型的研究进展，阿片受体及其杂寡体的配体结合和激活的结构基础得以进一步探索，新一代阿片类止痛药的合理设计也成为可能。为了实现这些长期目标，本文提出了一项专注于以下具体目标的研究工作：(1)建立处于活动状态的u阿片受体和处于非活动状态的Delta阿片受体的三维模型，并使用增强的构象采样方法改进这些模型(2)通过从配体-受体复合体的结构预测来开发与u受体的配体结合和激活以及在Delta受体上的结合和拮抗活性的药物载体(3)在已有知识的基础上，设计、合成、并评估具有改进的结合和活性图谱的新配体，并在实验确定的活性图谱的基础上改进和评估模型，以及(4)探索对u-Delta杂二聚体配合物的结构进行建模，以深入了解这种相互作用赋予这些配合物的新的结合位点特征。因此，拟议中的研究将加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，并增加设计和开发新的改进配体的前景，这些改进的配体有可能成为有效的止痛药，无严重副作用。公共卫生相关性：严重和慢性疼痛是一种使人虚弱的医疗状况，对大量个人的健康和福祉有巨大影响。虽然阿片类药物是有效的止痛药，但它们的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建模，以使设计和发现新的、有效的阿片类止痛化合物没有与当前药物相关的有限副作用。

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.