Discovery of benzo[cd]indol-2-one and benzylidene-thiazolidine-2,4-dione as new classes of NLRP3 inflammasome inhibitors via ER-β structure based virtual screening
Discovery of benzo[cd]indol-2-one and benzylidene-thiazolidine-2,4-dione as new classes of NLRP3 inflammasome inhibitors via ER-β structure based virtual screening
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DOI：
10.1016/j.bioorg.2019.103500
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发表时间：
2020-01-01
影响因子：
5.1
通讯作者：
Bharate, Sandip B.
中科院分区：
文献类型：
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作者：
Abdullaha, Mohd;Ali, Mehboob;Bharate, Sandip B.
结构导向的虚拟筛选技术已被证明是一种成功的筛选生物靶点支架的方法。NLRP 3炎性体的过度活性与包括阿尔茨海默病在内的多种炎性疾病有关。雌激素受体β（ER-β）活性的上调与NLRP 3炎性体活性的抑制直接相关。在本研究中，我们报告了通过ER-β晶体结构（PDB：5 TOA）引导的20，000个化合物库的虚拟筛选发现新的NLRP 3炎性体抑制剂。对于实验验证，基于结构新奇、对接评分、引物MMGB/SA结合亲和力和相互作用模式分析选择前10个配体。在所测试的化合物中，三种噻唑烷-4-酮IIIM-1268、IIIM-1269和IIIM-1270以及苯并[cd]吲哚-2-酮IIIM-1266在10 μ M时对小鼠巨噬细胞（J774A.1细胞）中IL-1 β释放的抑制率为73%、69%、75%和77%。亚苄基-噻唑烷-2，4-二酮IIIM-1268和IIIM-1270抑制IL-1 β释放，IC 50为2.3和3.5 μ M，并且在蛋白质印迹分析中也显著降低了IL-1 β成熟形式的蛋白质表达水平。IIIM-1266和IIIM-1270与ER-β活性位点的Arg 346和Glu 305残基形成双齿氢键，并强烈占据NLRP 3蛋白的ADP结合位点。本文呈现的结果表明，ER-β引导的VS可以成功地用于鉴定新的NLRP 3炎性体抑制剂，其可能在新型抗阿尔茨海默病剂的开发中具有潜力。
The structure-guided virtual screening (VS) has proved to be successful strategy in identification of new scaffolds for biological targets. The overactivity of NLRP3 inflammasome has been implicated in variety of inflammatory diseases including Alzheimer's disease. The up-regulation of estrogen-receptor beta (ER-beta) activity has been directly linked with inhibition of NLRP3 inflammasome activity. In the present study, we report discovery of new NLRP3 inflammasome inhibitors via ER-beta crystal structure (PDB: 5TOA) guided virtual screening of 20,000 compound library. For experimental validation, top 10 ligands were selected based on structure novelty, docking score, prime MMGB/SA binding affinity and interaction pattern analysis. Amongst the tested compounds, three thiazolidin-4-ones IIIM-1268, IIIM-1269 and IIIM-1270 and benzo[cd]indol-2-one IIIM-1266 have shown 73, 69, 75 and 77% suppression of IL-1 beta release in mouse macrophages (J774A.1 cells) at 10 mu M. Benzylidene-thiazolidine-2,4-diones IIIM-1268 and IIIM-1270 inhibited IL-1 beta release with IC50 of 2.3 and 3.5 mu M and also significantly decreased the protein expression level of mature form of IL-1 beta in western-blot analysis. IIIM-1266 and IIIM-1270 displayed bidentate H-bonding with Arg 346 and Glu 305 residues in the active site of ER-beta; and they also strongly occupied the ADP-binding site of NLRP3 protein. The results presented herein, indicate that ER-beta guided VS can be successfully used to identify new NLRP3 inflammasome inhibitors, which may have potential in the development of novel anti-Alzheimer agents.