Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

Huang Xi-Ping; Karpiak Joel; Kroeze Wesley K.; Zhu Hu; Chen Xin; Moy Sheryl S.; Saddoris Kara A.; Nikolova Viktoriya D.; Farrell Martilias S.; Wang Sheng; Mangano Thomas J.; Deshpande Deepak A.; Jiang Alice; Penn Raymond B.; Jin Jian; Koller Beverly H.; Kenakin Terry; Shoichet Brian K.; Roth Bryan L.

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Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

机译：黑暗药理学受体GPR68和GPR65的变构配体

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At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.

机译：人类基因组中至少有120个非嗅觉的G蛋白偶联受体是“孤儿”，其内源性配体是未知的，许多受体没有选择性配体，这阻碍了其生物学功能和临床相关性的确定。其中之一是质子受体GPR68，该质子受体缺乏用于探测其生物学的小分子调节剂。使用针对GPR68的基于酵母的筛选，此处我们将苯二氮卓类药物劳拉西m确定为非选择性GPR68阳性变构调节剂。改进了3,000多个GPR68同源模型，以在推定的变构位点识别劳拉西m。对接310万个分子预测了新的GPR68调节剂，其中许多已在功能测定中得到证实。一种有效的GPR68调节剂ogerin可抑制野生型恐惧条件下的回忆，但不能抑制GPR68敲除小鼠。相同的方法导致发现了GPR65的变构激动剂和负变构调节剂。结合基于物理和基于结构的筛选对于研究不足和孤立的GPCR的配体发现可能广泛有用。

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《Nature》 |2015年第7579期|477-483|共7页
作者
Huang Xi-Ping; Karpiak Joel; Kroeze Wesley K.; Zhu Hu; Chen Xin; Moy Sheryl S.; Saddoris Kara A.; Nikolova Viktoriya D.; Farrell Martilias S.; Wang Sheng; Mangano Thomas J.; Deshpande Deepak A.; Jiang Alice; Penn Raymond B.; Jin Jian; Koller Beverly H.; Kenakin Terry; Shoichet Brian K.; Roth Bryan L.;
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Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA|Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA;

Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA;

Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA;

Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA;

Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery CICBDD, Chapel Hill, NC 27599 USA|Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA;

Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA|Univ N Carolina, Carolina Inst Dev Disabil CIDD, Chapel Hill, NC 27599 USA;

Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA|Univ N Carolina, Carolina Inst Dev Disabil CIDD, Chapel Hill, NC 27599 USA;

Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA|Univ N Carolina, Carolina Inst Dev Disabil CIDD, Chapel Hill, NC 27599 USA;

Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA;

Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA;

Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA|Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA;

Thomas Jefferson Univ, Ctr Translat Med, Philadelphia, PA 19107 USA|Thomas Jefferson Univ, Dept Med, Philadelphia, PA 19107 USA;

Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA|Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA;

Thomas Jefferson Univ, Ctr Translat Med, Philadelphia, PA 19107 USA|Thomas Jefferson Univ, Dept Med, Philadelphia, PA 19107 USA;

Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery CICBDD, Chapel Hill, NC 27599 USA|Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA;

Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA;

Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA;

Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA;

Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA|Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA|Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

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