Discovery of μ,δ-Opioid Receptor Dual-Biased Agonists That Overcome the Limitation of Prior Biased Agonists,ACS Pharmacology & Translational Science

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Discovery of μ,δ-Opioid Receptor Dual-Biased Agonists That Overcome the Limitation of Prior Biased Agonists
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-04-06 , DOI: 10.1021/acsptsci.1c00044
Jin Hee Lee ₁ , Suh-Youn Shon ₁ , Woojin Jeon ₁ , Sung-Jun Hong ₁ , Junsu Ban ₁ , Do Sup Lee ₁

Affiliation

Morphine is widely used in pain management although the risk of side effects is significant. The use of biased agonists to the G protein of μ-opioid receptors has been suggested as a potential solution, although oliceridine and PZM21 have previously failed to demonstrate benefits in clinical studies. An amplification-induced confusion in the process of comparing G protein and beta-arrestin pathways may account for previously biased agonist misidentification. Here, we have devised a strategy to discover biased agonists with intrinsic efficacy. We computationally simulated 430 000 molecular dockings to the μ-opioid receptor to construct a compound library. Hits were then verified experimentally. Using the verified compounds, we performed simulations to build a second library with a common scaffold and selected compounds that showed a bias to μ- and δ-opioid receptors in a cell-based assay. Three compounds (ID110460001, ID110460002, and ID110460003) with a dual-biased agonistic effect for μ- and δ-opioid receptors were identified. These candidates are full agonists for the μ-opioid receptor and show specific binding modes. On the basis of our findings, we expect our novel compounds to act as more biased agonists compared to existing drugs, including oliceridine.

中文翻译：

μ,δ-阿片受体双重偏向激动剂的发现，克服了先前偏向激动剂的限制

吗啡广泛用于疼痛管理，尽管副作用的风险很大。有人建议对 μ-阿片受体的 G 蛋白使用偏向激动剂作为一种潜在的解决方案，尽管 oliceridine 和 PZM21 以前未能在临床研究中证明其益处。在比较 G 蛋白和 β-arrestin 途径的过程中，扩增引起的混淆可能是以前有偏见的激动剂错误识别的原因。在这里，我们设计了一种策略来发现具有内在功效的偏向激动剂。我们计算模拟了 430 000 个与 μ-阿片受体的分子对接，以构建化合物库。然后通过实验验证命中。使用经过验证的化合物，我们进行了模拟以建立第二个库，该库具有通用支架和选定的化合物，这些化合物在基于细胞的测定中显示出对 μ- 和 δ-阿片受体的偏向。鉴定了三种化合物（ID110460001、ID110460002 和 ID110460003）对 μ-和 δ-阿片受体具有双重激动作用。这些候选物是 μ-阿片受体的完全激动剂，并显示出特异性结合模式。根据我们的研究结果，我们希望我们的新型化合物与现有药物（包括 oliceridine）相比，可以作为更具偏向性的激动剂。

更新日期：2021-06-11

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