Identification of N-phenyl-2-(N-phenylphenylsulfonamido) acetamides as new ROR gamma inverse agonists: Virtual screening, structure-based optimization, and biological evaluation
Identification of N-phenyl-2-(N-phenylphenylsulfonamido) acetamides as new ROR gamma inverse agonists: Virtual screening, structure-based optimization, and biological evaluation
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鉴定 N-苯基-2-(N-苯基苯基磺酰胺基) 乙酰胺作为新的 ROR γ 反激动剂：虚拟筛选、基于结构的优化和生物学评估
DOI：
10.1016/j.ejmech.2016.03.052
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发表时间：
2016
影响因子：
6.7
通讯作者：
Xu Yong
中科院分区：
文献类型：
--
作者：
Song Yu;Xue Xiaoqian;Wu Xishan;Wang Rui;Xing Yanli;Yan Weiqun;Zhou Yulai;Qian Chao-Nan;Zhang Yan;Xu Yong
Retinoic acid receptor-related orphan receptors (RORs) are ligand-dependent transcriptional factors and members of the nuclear receptor superfamily. RORs regulate inflammation, metabolic disorders and circadian rhythm. RORγ is a promising therapeutic drug target for treating Th17-mediated autoimmune diseases. In our study, we performed structure-based virtual screening and ligand-based virtual screening targeting the RORγ ligand-binding domain and successfully identifiedN-phenyl-2-(N-phenylphenylsulfonamido) acetamides as a type of RORγ inverse agonist. Among the 28 purchased compounds, C11 was confirmed to be active with micromolar IC50values in both an AlphaScreen assay (62.58 μM) and a cell-based reporter gene assay (4.54 μM). Structure-guided optimization of the compoundC11led to the identification of compound39, which significantly enhanced RORγ inhibition with an IC50value of 630 nM. The RORγ antagonism of39was 7-fold higher than that of hit compoundC11. These results represent a promising starting point for developing potent small molecule RORγ inverse agonists for the treatment of autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.
