Jafari Fataneh, Nowroozi Amin, Shahlaei Mohsen
Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Nano Drug Delivery Research Center, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Iran J Pharm Res. 2018 Fall;17(4):1263-1287.
Glucagon and the glucagon receptor are most important molecules control over blood glucose concentrations. These two molecules are very important to studies of type 2 diabetic patients. In literature, several classes of small molecule antagonists of the human glucagon receptor have been reported. Glucagon receptor antagonist could decrease hepatic glucose output and improve glucose control in diabetic patients. In this research, to identify novel and diverse leads for use in potent glucagon receptor antagonist design, a ligand-based pharmacophore modeling, was developed using the best conformations of training set compounds. The best five features pharmacophore model, called Hypo1, includes, hydrogen bond acceptors, two hydrophobic, and positive ionizable features, which has the highest correlation coefficient (0.805), cost difference (64.38), low (2.148), as well as it shows a high goodness of fit and enrichment factor. The generated pharmacophore model has been validated by using a series of similar structures with varying affinities for the glucagon receptor. Then, the developed model has been applied as a search query in different database searching with the main objective of finding novel molecules which have the potential to be be modified into novel lead compounds. As a result, some hit molecules were introduced as final candidates by employing virtual screening and molecular docking procedure simultaneously. The results from pharmacophore modeling and molecular docking are complementary to each other and could serve as a useful way for the discovery of potent small molecules as glucagon receptor antagonist.
胰高血糖素和胰高血糖素受体是控制血糖浓度的最重要分子。这两种分子对2型糖尿病患者的研究非常重要。在文献中，已经报道了几类人胰高血糖素受体的小分子拮抗剂。胰高血糖素受体拮抗剂可以降低肝脏葡萄糖输出并改善糖尿病患者的血糖控制。在本研究中，为了确定用于高效胰高血糖素受体拮抗剂设计的新型多样的先导物，使用训练集化合物的最佳构象开发了基于配体的药效团模型。最佳的五元特征药效团模型Hypo1包括氢键受体、两个疏水特征和正离子化特征，其具有最高的相关系数（0.805）、成本差异（64.38）、较低的（2.148），并且显示出良好的拟合优度和富集因子。所生成的药效团模型已通过使用一系列对胰高血糖素受体具有不同亲和力的相似结构进行了验证。然后，所开发的模型已被用作不同数据库搜索中的搜索查询，主要目的是寻找有可能被修饰成新型先导化合物的新型分子。结果，通过同时采用虚拟筛选和分子对接程序，引入了一些命中分子作为最终候选物。药效团建模和分子对接的结果相互补充，可作为发现有效的小分子胰高血糖素受体拮抗剂的有用方法。
