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Structure Based Virtual Screening Studies to Identify Novel Potential Compounds for GPR142 and Their Relative Dynamic Analysis for Study of Type 2 Diabetes

机译:基于结构的虚拟筛选研究用于识别GPR142的新型潜在化合物以及用于2型糖尿病研究的相对动力学分析

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摘要

GPR142 (G protein receptor 142) is a novel orphan GPCR (G protein coupled receptor) belonging to “Class A” of GPCR family and expressed in β cells of pancreas. In this study, we reported the structure based virtual screening to identify the hit compounds which can be developed as leads for potential agonists. The results were validated through induced fit docking, pharmacophore modeling, and system biology approaches. Since, there is no solved crystal structure of GPR142, we attempted to predict the 3D structure followed by validation and then identification of active site using threading and ab initio methods. Also, structure based virtual screening was performed against a total of 1171519 compounds from different libraries and only top 20 best hit compounds were screened and analyzed. Moreover, the biochemical pathway of GPR142 complex with screened compound2 was also designed and compared with experimental data. Interestingly, compound2 showed an increase in insulin production via Gq mediated signaling pathway suggesting the possible role of novel GPR142 agonists in therapy against type 2 diabetes.
机译:GPR142(G蛋白受体142)是一种新型的孤儿GPCR(G蛋白偶联受体),属于GPCR家族的“ A类”,在胰腺β细胞中表达。在这项研究中,我们报道了基于结构的虚拟筛选,以鉴定可被开发为潜在激动剂的先导的命中化合物。通过诱导拟合对接,药效团建模和系统生物学方法验证了结果。由于没有解决的GPR142晶体结构,我们尝试预测3D结构,然后进行验证,然后使用穿线和从头算方法确定活性位点。此外,针对来自不同库的总共1171519种化合物进行了基于结构的虚拟筛选,仅筛选和分析了排名前20位的最佳命中化合物。此外,还设计了GPR142与被筛选化合物2复合物的生化途径,并与实验数据进行了比较。有趣的是,化合物2通过Gq介导的信号传导途径显示出胰岛素产生的增加,表明新型GPR142激动剂可能在抗2型糖尿病的治疗中发挥作用。

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