Identification of Small-Molecule Antagonists Targeting the Growth Hormone Releasing Hormone Receptor (GHRHR),Journal of Chemical Information and Modeling

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Identification of Small-Molecule Antagonists Targeting the Growth Hormone Releasing Hormone Receptor (GHRHR)
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-08-29 , DOI: 10.1021/acs.jcim.4c00577
Minos-Timotheos Matsoukas ₁ , Tarryn Radomsky _{2,

3} , Vasilis Panagiotopoulos ₁ , Robin du Preez _{2,

3} , Michail Papadourakis ₄ , Konstantinos Tsianakas ₁ , Robert P Millar _{2,

5,

6,

7} , Ross C Anderson _{2,

3} , Georgios A Spyroulias ₈ , Claire L Newton _{2,

5}

Affiliation

The growth hormone-releasing hormone receptor (GHRHR) belongs to Class B1 of G protein-coupled receptors (GPCRs). Class B1 GPCR peptides such, as growth hormone-releasing hormone (GHRH), have been proposed to bind in a two-step model, where first the C-terminal region of the peptide interacts with the extracellular domain of the receptor and, subsequently, the N-terminus interacts with the seven transmembrane domain of the receptor, resulting in activation. The GHRHR has recently been highlighted as a promising drug target toward several types of cancer and has been shown to be overexpressed in prostate, breast, pancreatic, and ovarian cancer. Indeed, peptide GHRHR antagonists have displayed promising results in many cancer models. However, no nonpeptide GHRHR-targeting compounds have yet been identified. We have utilized several computational tools to target GHRHR and identify potential small-molecule compounds directed at this receptor. These compounds were validated in vitro using a cyclic adenosine monophosphate (cAMP) ELISA to measure activity at the GHRHR. In vitro results suggest that several of the novel small-molecule compounds could inhibit GHRH-induced cAMP accumulation. Preliminary analysis of the specificity/selectivity of one of the most effective hit compounds indicated that the effect seen was via inhibition of the GHRHR. We therefore report the first nonpeptide antagonists of GHRHR and propose a structural basis for inhibition induced by the compounds, which may assist in the future design of lead GHRHR compounds for treating disorders attributed to dysregulated/aberrant GHRHR signaling.

中文翻译：

针对生长激素释放激素受体 (GHRHR) 的小分子拮抗剂的鉴定

生长激素释放激素受体 (GHRHR) 属于 G 蛋白偶联受体 (GPCR) B1 类。 B1 类 GPCR 肽，如生长激素释放激素 (GHRH)，已被提议在两步模型中结合，其中首先肽的 C 末端区域与受体的胞外结构域相互作用，随后， N 末端与受体的七个跨膜结构域相互作用，导致激活。 GHRHR 最近被强调为治疗多种癌症的有前景的药物靶点，并已被证明在前列腺癌、乳腺癌、胰腺癌和卵巢癌中过度表达。事实上，肽 GHRHR 拮抗剂在许多癌症模型中显示出有希望的结果。然而，尚未鉴定出非肽 GHRHR 靶向化合物。我们利用多种计算工具来靶向 GHRHR 并识别针对该受体的潜在小分子化合物。使用环磷酸腺苷 (cAMP) ELISA 测量 GHRHR 活性，对这些化合物进行了体外验证。体外结果表明，几种新型小分子化合物可以抑制 GHRH 诱导的 cAMP 积累。对最有效的命中化合物之一的特异性/选择性的初步分析表明，所看到的效果是通过抑制 GHRHR 实现的。因此，我们报告了第一个 GHRHR 非肽拮抗剂，并提出了由这些化合物诱导的抑制的结构基础，这可能有助于未来设计用于治疗由失调/异常 GHRHR 信号传导引起的疾病的先导 GHRHR 化合物。

更新日期：2024-08-29

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