Rational discovery of new DOR chemotypes to prevent addiction and overdose

 描述（由申请人提供）：阿片类镇痛药是疼痛管理中最有效的工具;然而，高耐受性和成瘾倾向也使其成为最滥用的药物类别，每年在美国导致数百万例药物过量和超过15，000例死亡。特异性调节d-阿片受体（DOR）是控制阿片类药物耐受性和成瘾性的最有前途的策略之一;然而，只有少数化学型的DOR选择性化合物已被探索。阿片受体的结构表征，包括DOR/纳曲吲哚复合物在1.8 nm处的新的高分辨率结构，以及DOR与双功能肽DIPP-NH 2的结构，使得通过发现具有所需功能特征的新化学型来扩展DOR化合物库的新的独特机会成为可能。这些结构揭示了配体结合的原子细节，并为合理发现靶向DOR的正构或变构口袋的新配体提供了可靠的3D框架。该项目将主要关注两种治疗有益的概况：（a）已知可减少阿片类药物治疗耐受性和副作用的双功能莫尔激动剂/DOR拮抗剂，和（B）仅在内源性阿片类药物存在下调节DOR活性的变构配体。在该项目的探索性R21阶段，我们将对超过600万种可用化合物进行大规模基于结构的虚拟配体筛选，以选择小的候选命中集，然后通过实验测试和识别新的双功能和变构配体。最有前途的化学支架和经验证的结构模型将用于R33阶段的迭代铅优化。初始筛选和先导物优化阶段都将采用最先进的基于结构的方法，这些方法在最近的GPCR应用中已被证明非常有效。该计划的成功将导致对药物作用的新见解，导致具有所需特性的新DOR配体，并为基于合理结构的更安全和更少成瘾性的阿片类药物疗法的发现建立坚实的平台。

 DESCRIPTION (provided by applicant): Opioid analgesics are the most efficient tool in pain management; however, high tolerance and addiction liabilities also make them the most abused class of medication, resulting in millions of cases of drug overdose and more than 15,000 deaths in the US each year. Specific modulation of d-opioid receptor (DOR) represents one of the most promising strategies to control tolerance and addiction to opioid drugs; however, only a few chemotypes of DOR-selective compounds have been explored. A new unique opportunity to expand the repertoire of DOR compounds by discovery of novel chemotypes with desirable functional profiles is enabled by structural characterization of opioid receptors, including new high resolution structures of DOR/naltrindole complex at 1.8 Å, and DOR with bifunctional peptide DIPP-NH2. The structures reveal atomic details of ligand binding and provide a reliable 3D framework for rational discovery of new ligands targeting orthosteric or allosteric pockets of DOR. The project will primarily focus on two therapeutically beneficial profiles: (a) bifunctional MOR agonists/DOR antagonists known to reduce tolerance and side effects of opioid therapy, and (b) allosteric ligands that modulate DOR activity only in the presence of endogenous opioid. In the exploratory R21 phase of the project we will perform large scale structure-based virtual ligand screening of more than 6 million available compounds to select small sets of candidate hits, and then experimentally test and identify new bifunctional and allosteric ligands. The most promising chemical scaffolds, and validated structural models will be employed then in an iterative lead optimization at the R33 phase. Both initial screening and lead optimization phases will employ state-of-the-art structure-based approaches which have proven to be highly effective in recent applications to GPCRs. Success of the program will result in new insights into drug action, lead to new DOR ligands with desired properties, and establish a solid platform for rational structure-based discovery of safer and less addictive opioid therapies.