In silico design of novel probes for the atypical opioid receptor MRGPRX2.
In silico design of novel probes for the atypical opioid receptor MRGPRX2.
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DOI：
10.1038/nchembio.2334
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发表时间：
2017-05
影响因子：
14.8
通讯作者：
Roth BL
中科院分区：
文献类型：
--
作者：
Lansu K;Karpiak J;Liu J;Huang XP;McCorvy JD;Kroeze WK;Che T;Nagase H;Carroll FI;Jin J;Shoichet BK;Roth BL
灵长类动物特有的MRGPRX2 G蛋白偶联受体（GPCR）被认为可调节疼痛和瘙痒。尽管有假定的肽类和小分子MRGPRX2激动剂，但具有纳摩尔选择性效力的探针尚未见报道。为了确定一种MRGPRX2探针，我们首先筛选了5695种小分子，发现许多阿片类化合物可激活MRGPRX2，包括（-）-和（+）-吗啡、氢可酮、青藤碱、右美沙芬以及强啡肽原衍生的肽类，如强啡肽A、强啡肽B以及α-和β-新内啡肽。我们利用这些信息来选择经诱变验证的同源模型，并对近400万个小分子进行了对接。通过这种对接，我们预测出ZINC - 3573，它是一种强效的MRGPRX2选择性激动剂，对315种其他GPCR和97种代表性激酶几乎没有活性，并且其对映异构体基本无活性。ZINC - 3573可激活人肥大细胞系中的内源性MRGPRX2，诱导脱颗粒和钙释放。MRGPRX2是一种独特的非典型类阿片受体，对调节肥大细胞脱颗粒很重要，现在可以用ZINC - 3573对其进行特异性调节。
The primate-exclusive MRGPRX2 G protein-coupled receptor (GPCR) has been suggested to modulate pain and itch. Despite putative peptide and small molecule MRGPRX2 agonists, selective nanomolar potency probes have not yet been reported. To identify a MRGPRX2 probe, we first screened 5,695 small molecules and found many opioid compounds activated MRGPRX2, including (−)- and (+)-morphine, hydrocodone, sinomenine, dextromethorphan and the prodynorphin-derived peptides, dynorphin A, dynorphin B, and α- and β-neoendorphin. We used these to select for mutagenesis-validated homology models and docked almost 4 million small molecules. From this docking, we predicted ZINC-3573, which represents a potent MRGPRX2-selective agonist, showing little activity against 315 other GPCRs and 97 representative kinases, and an essentially inactive enantiomer. ZINC-3573 activates endogenous MRGPRX2 in a human mast cell line inducing degranulation and calcium release. MRGPRX2 is a unique atypical opioid-like receptor important for modulating mast cell degranulation, which can now be specifically modulated with ZINC-3573.