Discovery of a potential positive allosteric modulator of glucagon-like peptide 1 receptor through virtual screening and experimental study
Discovery of a potential positive allosteric modulator of glucagon-like peptide 1 receptor through virtual screening and experimental study
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DOI：
10.1007/s10822-019-00254-4
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发表时间：
2019-11-22
影响因子：
3.5
通讯作者：
Li, Zhijun
中科院分区：
文献类型：
--
作者：
Redij, Tejashree;Ma, Jian;Li, Zhijun
胰高血糖素样肽1受体（GLP-1 R）是治疗2型糖尿病的公认靶点，基于GLP-1 R激动剂的治疗代表了一种有效的方法，可产生多种GLP-1类似物药物。然而，靶向GLP-1 R的非肽激动剂药物的开发仍然不成功。一个有前途的策略旨在开发口服生物可利用的小分子GLP 1 - 1 R正变构调节剂。利用最近报道的GLP-1 R在其活性状态下的cryo-EM结构，我们进行了基于结构的筛选研究，包括潜在的变构结合位点预测和药物样化合物的计算机模拟筛选，并进行了体外测试和位点特异性诱变研究。一种低分子量化合物被确认为GLP-1 R的正变构调节剂，因为其以剂量依赖性方式增强GLP-1对人GLP-1 R的亲和力和功效。该化合物还与GLP-1协同刺激胰岛素分泌。该化合物的分子量为399，是已知最小的GLP-1 R PAM之一，并显示出其他有利的药物样性质。位点特异性诱变研究证实，该化合物的结合位点与跨膜结构域中的已知拮抗剂的结合位点部分重叠。这些结果表明，基于结构的方法是有用的发现GLP-1 R的非肽变构调节剂，这里报道的化合物是有价值的进一步药物开发。
The Glucagon-like peptide 1 receptor (GLP-1R) is a well-established target for the treatment of type 2 diabetes and GLP-1R agonist-based therapies represent an effective approach which results in several GLP-1 analog drugs. However, the development of nonpeptidic agonist drugs targeting GLP-1R remains unsuccessful. A promising strategy aims to develop orally bioavailable, small-molecule positive allosteric modulators of GLP1-1R. Taking advantage of the recently reported cryo-EM structure of GLP-1R at its active state, we have performed structure-based screening studies which include potential allosteric binding site prediction and in silico screening of drug-like compounds, and conducted in vitro testing and site-specific mutagenesis studies. One compound with low molecular weight was confirmed as a positive allosteric modulator of GLP-1R as it enhances GLP-1 ' s affinity and efficacy to human GLP-1R in a dose dependent manner. This compound also stimulates insulin secretion synergistically with GLP-1. With the molecular weight of 399, this compound represents one of the smallest known GLP-1R PAMs, and demonstrates other favorable drug-like properties. Site-specific mutagenesis studies confirmed that the binding site of this compound partially overlaps with that of a known antagonist in the transmembrane domain. These results demonstrate that structure-based approach is useful for discovering nonpeptidic allosteric modulators of GLP-1R and the compound reported here is valuable for further drug development.