Abstract

Glucagon-like peptide-1 (GLP-1) is involved in glucose-stimulated insulin secretion and weight regulating actions through the activation of the GLP-1 receptor (GLP-1R). Clinical effectiveness of GLP-1 mimetics is effective in improving glucose control in patients. Thus, identifying and developing orally active small-molecule agonists are highly desirable. This study summarizes the structure-function relationship of hGLP-1R through computational approaches and search of small molecule GLP-1R agonists. We carried out mutation guided data-driven study, for developing the GLP-1R model to explore and validate the putative site for quinoxaline analogues. The developed GLP-1R homology model was subjected to 500 ns MD simulation for validation. Various snapshots were considered to identify the best structure of GLP-1R based on correlation between experimental pEC₅₀ and various theoretical parameters (docking score, MM-GBSA ΔG bind, WM/MM ΔG bind). The putative binding site (Sitemap and WaterMap has been predicted and it matched well with the available data. Excellent correlation (R² =0.94), between pEC50 and WM/MM ΔG bind for the snapshot at 350 ns was observed after including induced-fit docking results of the most potent molecule. Enrichment calculation indicates better AUC (=0.75) for predicted complex structure. A comparison of the developed GLP-1R model with the available crystal structure shows excellent similarities and it was used for virtual screening to find small molecule agonists. The good correlation of our model with crystal structures of GLP-1R may help to understand the structure-function relationship of other secretin families.

摘要

胰高血糖素样肽-1 (GLP-1) 通过激活 GLP-1 受体 (GLP-1R) 参与葡萄糖刺激的胰岛素分泌和体重调节作用。GLP-1 模拟物的临床有效性可有效改善患者的血糖控制。因此，非常需要鉴定和开发口服活性小分子激动剂。本研究通过计算方法和小分子 GLP-1R 激动剂的搜索总结了 hGLP-1R 的结构-功能关系。我们进行了突变引导的数据驱动研究，以开发 GLP-1R 模型以探索和验证喹喔啉类似物的推定位点。开发的 GLP-1R 同源模型经过 500 ns MD 模拟进行验证。₅₀和各种理论参数（对接分数、MM-GBSA ΔG 结合、WM/MM ΔG 结合）。推定的结合位点（Sitemap 和 WaterMap 已被预测，并且与可用数据很好地匹配。在包含诱导拟合后，观察到 pEC50 和 WM/MM ΔG 结合在 350 ns 的快照之间具有出色的相关性（R ² = 0.94）最有效分子的对接结果。富集计算表明预测的复杂结构更好的AUC（=0.75）。开发的GLP-1R模型与现有晶体结构的比较显示出极好的相似性，用于虚拟筛选寻找小分子我们的模型与 GLP-1R 晶体结构的良好相关性可能有助于理解其他促胰液素家族的结构-功能关系。