当前位置: X-MOL 学术Mol. Divers. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Prospect of Anterior Gradient 2 homodimer inhibition via repurposing FDA-approved drugs using structure-based virtual screening
Molecular Diversity ( IF 3.8 ) Pub Date : 2021-06-28 , DOI: 10.1007/s11030-021-10263-x
Shafi Ullah 1 , Shafi Ullah Khan 2, 3 , Abbas Khan 4 , Muhammad Junaid 5 , Humaira Rafiq 5 , Thet Thet Htar 2 , Yaxue Zhao 1 , Syed Adnan Ali Shah 6 , Abdul Wadood 5
Affiliation  

Anterior Gradient 2 (AGR2) has recently been reported as a tumor biomarker in various cancers, i.e., breast, prostate and lung cancer. Predominantly, AGR2 exists as a homodimer via a dimerization domain (E60-K64); after it is self-dimerized, it helps FGF2 and VEGF to homo-dimerize and promotes the angiogenesis and the invasion of vascular endothelial cells and fibroblasts. Up till now, no small molecule has been discovered to inhibit the AGR2–AGR2 homodimer. Therefore, the present study was performed to prepare a validated 3D structure of AGR2 by homology modeling and discover a small molecule by screening the FDA-approved drugs library on AGR2 homodimer as a target protein. Thirteen different homology models of AGR2 were generated based on different templates which were narrowed down to 5 quality models sorted by their overall Z-scores. The top homology model based on PDB ID = 3PH9 was selected having the best Z-score and was further assessed by Verify-3D, ERRAT and RAMPAGE analysis. Structure-based virtual screening narrowed down the large library of FDA-approved drugs to ten potential AGR2–AGR2 homodimer inhibitors having FRED score lower than − 7.8 kcal/mol in which the top 5 drugs’ binding stability was counter-validated by molecular dynamic simulation. To sum up, the present study prepared a validated 3D structure of AGR2 and, for the first time reported the discovery of 5 FDA-approved drugs to inhibit AGR2–AGR2 homodimer by using structure-based virtual screening. Moreover, the binding of the top 5 hits with AGR2 was also validated by molecular dynamic simulation.

Graphic abstract

A validated 3D structure of Anterior Gradient 2 (AGR2) was prepared by homology modeling, which was used in virtual screening of FDA-approved drugs library for the discovery of prospective inhibitors of AGR2–AGR2 homodimer.



中文翻译:

使用基于结构的虚拟筛选重新利用 FDA 批准的药物抑制前梯度 2 同源二聚体的前景

前梯度 2 (AGR2) 最近已被报道为各种癌症(即乳腺癌、前列腺癌和肺癌)中的肿瘤生物标志物。主要地,AGR2 通过二聚结构域 (E60-K64) 作为同二聚体存在;自身二聚化后,帮助FGF2和VEGF同源二聚化,促进血管生成,促进血管内皮细胞和成纤维细胞的侵袭。到目前为止,还没有发现抑制 AGR2-AGR2 同型二聚体的小分子。因此,本研究旨在通过同源性建模制备经过验证的 AGR2 3D 结构,并通过筛选 FDA 批准的以 AGR2 同源二聚体为靶蛋白的药物库来发现小分子。基于不同的模板生成了 13 个不同的 AGR2 同源模型,这些模型根据它们的整体 Z 分数缩小到 5 个质量模型。选择基于 PDB ID = 3PH9 的顶级同源模型具有最佳 Z 分数,并通过 Verify-3D、ERRAT 和 RAMPAGE 分析进一步评估。基于结构的虚拟筛选将 FDA 批准的药物的大型库缩小到 10 个潜在的 AGR2-AGR2 同二聚体抑制剂,其 FRED 评分低于 - 7.8 kcal/mol,其中前 5 种药物的结合稳定性通过分子动力学模拟得到反验证. 综上所述,本研究制备了经过验证的 AGR2 3D 结构,并首次报道了通过基于结构的虚拟筛选发现了 5 种 FDA 批准的药物来抑制 AGR2-AGR2 同源二聚体。此外,前 5 个命中与 AGR2 的结合也通过分子动力学模拟得到验证。错误和 RAMPAGE 分析。基于结构的虚拟筛选将 FDA 批准的药物的大型库缩小到 10 个潜在的 AGR2-AGR2 同二聚体抑制剂,其 FRED 评分低于 - 7.8 kcal/mol,其中前 5 种药物的结合稳定性通过分子动力学模拟得到反验证. 综上所述,本研究制备了经过验证的 AGR2 3D 结构,并首次报道了通过基于结构的虚拟筛选发现了 5 种 FDA 批准的药物来抑制 AGR2-AGR2 同源二聚体。此外,前 5 个命中与 AGR2 的结合也通过分子动力学模拟得到验证。错误和 RAMPAGE 分析。基于结构的虚拟筛选将 FDA 批准的药物的大型库缩小到 10 个潜在的 AGR2-AGR2 同二聚体抑制剂,其 FRED 评分低于 - 7.8 kcal/mol,其中前 5 种药物的结合稳定性通过分子动力学模拟得到反验证. 综上所述,本研究制备了经过验证的 AGR2 3D 结构,并首次报道了通过基于结构的虚拟筛选发现了 5 种 FDA 批准的药物来抑制 AGR2-AGR2 同源二聚体。此外,前 5 个命中与 AGR2 的结合也通过分子动力学模拟得到验证。8 kcal/mol,其中前5种药物的结合稳定性通过分子动力学模拟得到反验证。综上所述,本研究制备了经过验证的 AGR2 3D 结构,并首次报道了通过基于结构的虚拟筛选发现了 5 种 FDA 批准的药物来抑制 AGR2-AGR2 同源二聚体。此外,前 5 个命中与 AGR2 的结合也通过分子动力学模拟得到验证。8 kcal/mol,其中前5种药物的结合稳定性通过分子动力学模拟得到反验证。综上所述,本研究制备了经过验证的 AGR2 3D 结构,并首次报道了通过基于结构的虚拟筛选发现了 5 种 FDA 批准的药物来抑制 AGR2-AGR2 同源二聚体。此外,前 5 个命中与 AGR2 的结合也通过分子动力学模拟得到验证。

图形摘要

通过同源性建模制备了经过验证的前梯度 2 (AGR2) 3D 结构,用于虚拟筛选 FDA 批准的药物库,以发现 AGR2-AGR2 同源二聚体的潜在抑制剂。

更新日期:2021-06-28
down
wechat
bug