title: Identification of N-phenyl-2-(N-phenylphenylsulfonamido)acetamides as new RORγ inverse agonists: Virtual screening, structure-based optimization, and biological evaluation.
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.
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Xue
authors.affiliation: 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.
authors.forename: Xishan
authors.initials: X
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Bioengineering, School of Pharmaceutical Sciences, Jilin University, No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China.
authors.forename: Weiqun
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Bioengineering, School of Pharmaceutical Sciences, Jilin University, No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China.
authors.forename: Yulai
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Chao-Nan
authors.initials: CN
authors.lastname: Qian
authors.affiliation: 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: zhang_yan2012@gibh.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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: xu_yong@gibh.ac.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000081:Acetamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000595:Amino Acid Sequence; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D054314:Drug Inverse Agonism; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D000081:Acetamides; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3
keywords: Autoimmune diseases; Inverse agonist; Molecular docking; Nuclear receptor; RORγ; Similarity-based screening; Virtual screening