Development of CXCR4 modulators by virtual HTS of a novel amide-sulfamide compound library.
Development of CXCR4 modulators by virtual HTS of a novel amide-sulfamide compound library.
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通过新型酰胺 - 硫酰胺化合物库的虚拟HTS开发CXCR4调节剂。
DOI：
10.1016/j.ejmech.2016.11.026
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发表时间：
2017-01-27
影响因子：
6.7
通讯作者：
Shim H
中科院分区：
文献类型：
--
作者：
Bai R;Shi Q;Liang Z;Yoon Y;Han Y;Feng A;Liu S;Oum Y;Yun CC;Shim H
在疾病过程开始时，CXCR4在将炎症细胞募集到炎症部位中起着至关重要的作用。调节CXCR4功能为抗炎策略提供了新的途径。然而，长期使用CXCR4拮抗剂由于其干细胞动员特性而存在潜在的严重副作用。我们一直在开发不具有这种特性的部分CXCR4拮抗剂。新的计算机辅助药物设计程序FRESH工作流用于抗CXCR4先导化合物的发现和优化，该程序将化合物库的构建和CXCR4对接屏幕结合在一起。基于设计的母体框架，经过系统过滤和对接筛选，得到30个优先的酰胺-亚胺结构。从前30位化合物中共分离得到12个化合物。大多数合成的化合物对CXCR4具有良好至优异的结合亲和力。化合物Ig和Im对二甲苯诱导的小鼠耳部炎症有明显的抑制作用（分别抑制56%和54%）。Western blot分析显示，Ig显著阻断CXCR4/ cxcl12介导的Akt磷酸化。此外，Ig降低致病性大肠杆菌感染巨噬细胞分泌TNF-α的量。更重要的是，Ig没有明显的细胞毒性。研究结果表明，FRESH虚拟高通量筛选程序可以成功发现有效的先导化合物，酰胺-氨基磺胺药效团是阻断CXCR4功能的新型有效框架。
CXCR4 plays a crucial role in recruitment of inflammatory cells to inflammation sites at the beginning of the disease process. Modulating CXCR4 functions presents a new avenue for anti-inflammatory strategies. However, using CXCR4 antagonists for a long term usage presents potential serious side effect due to their stem cell mobilizing property. We have been developing partial CXCR4 antagonists without such property. A new computer-aided drug design program, the FRESH workflow, was used for anti-CXCR4 lead compound discovery and optimization, which coupled both compound library building and CXCR4 docking screens in one campaign. Based on the designed parent framework, 30 prioritized amide-sulfamide structures were obtained after systemic filtering and docking screening. Twelve compounds were prepared from the top-30 list. Most synthesized compounds exhibited good to excellent binding affinity to CXCR4. Compounds Ig and Im demonstrated notable in vivo suppressive activity against xylene-induced mouse ear inflammation (with 56% and 54% inhibition). Western blot analyses revealed that Ig significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, Ig attenuated the amount of TNF-α secreted by pathogenic E. coli-infected macrophages. More importantly, Ig had no observable cytotoxicity. Our results demonstrated that FRESH virtual high throughput screening program of targeted chemical class could successfully find potent lead compounds, and the amide-sulfamide pharmacophore was a novel and effective framework blocking CXCR4 function.