Department of Medicinal Chemistry, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
School of Pharmacy - Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia.
Mol Divers. 2022 Jun;26(3):1399-1409. doi: 10.1007/s11030-021-10263-x. Epub 2021 Jun 28.
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. 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.
先前梯度 2（AGR2）最近被报道为多种癌症的肿瘤标志物，如乳腺癌、前列腺癌和肺癌。主要通过二聚化结构域（E60-K64），AGR2 存在为同源二聚体；自我二聚化后，它有助于 FGF2 和 VEGF 同源二聚化，并促进血管内皮细胞和成纤维细胞的血管生成和侵袭。到目前为止，尚未发现能够抑制 AGR2-AGR2 同源二聚体的小分子。因此，本研究通过同源建模制备了 AGR2 的验证 3D 结构，并通过筛选 FDA 批准药物库中的小分子作为靶蛋白来发现 AGR2 同源二聚体的小分子。基于不同模板生成了 13 种不同的 AGR2 同源模型，根据总体 Z 分数将其缩小到 5 个质量模型。基于 PDB ID = 3PH9 的最佳同源模型具有最佳 Z 分数，并进一步通过 Verify-3D、ERRAT 和 RAMPAGE 分析进行评估。基于结构的虚拟筛选将庞大的 FDA 批准药物库缩小到 10 种具有 FRED 评分低于-7.8 kcal/mol 的潜在 AGR2-AGR2 同源二聚体抑制剂，其中前 5 种药物的结合稳定性通过分子动力学模拟进行了验证。总之，本研究制备了 AGR2 的验证 3D 结构，并首次报道了使用基于结构的虚拟筛选发现 5 种 FDA 批准的药物来抑制 AGR2-AGR2 同源二聚体。此外，还通过分子动力学模拟验证了前 5 个命中物与 AGR2 的结合。通过同源建模制备了先前梯度 2（AGR2）的验证 3D 结构，用于筛选 FDA 批准药物库，以发现 AGR2-AGR2 同源二聚体的潜在抑制剂。
