2. Academic Validation
  3. Identification of N-phenyl-2-(N-phenylphenylsulfonamido)acetamides as new RORγ inverse agonists: Virtual screening, structure-based optimization, and biological evaluation

Identification of N-phenyl-2-(N-phenylphenylsulfonamido)acetamides as new RORγ inverse agonists: Virtual screening, structure-based optimization, and biological evaluation

  • Eur J Med Chem. 2016 Jun 30;116:13-26. doi: 10.1016/j.ejmech.2016.03.052.
Yu Song 1,  Xiaoqian Xue 2,  Xishan Wu 3,  Rui Wang 2,  Yanli Xing 1,  Weiqun Yan 4,  Yulai Zhou 4,  Chao-Nan Qian 5,  Yan Zhang 6,  Yong Xu 7
Affiliations

Affiliations

  • 1 Department of Bioengineering, School of Pharmaceutical Sciences, Jilin University, No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China; Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.
  • 2 Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
  • 3 Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China; Department of Natural Medicinal Chemistry, China Pharmaceutical University, No. 639 Longmian Road, Jiangning District, Nanjing 211198, China.
  • 4 Department of Bioengineering, School of Pharmaceutical Sciences, Jilin University, No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China.
  • 5 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
  • 6 Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China. Electronic address: [email protected].
  • 7 Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China. Electronic address: [email protected].
PMID: 27043267 DOI: 10.1016/j.ejmech.2016.03.052
Abstract

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 identified N-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 IC50 values in both an AlphaScreen assay (62.58 μM) and a cell-based reporter gene assay (4.54 μM). Structure-guided optimization of the compound C11 led to the identification of compound 39, which significantly enhanced RORγ inhibition with an IC50 value of 630 nM. The RORγ antagonism of 39 was 7-fold higher than that of hit compound C11. 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.

Keywords

Autoimmune diseases; Inverse agonist; Molecular docking; Nuclear receptor; RORγ; Similarity-based screening; Virtual screening.

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