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. Epub 2016 Mar 21.


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.

MeSH terms

  • Acetamides / chemistry*
  • Acetamides / metabolism
  • Acetamides / pharmacology*
  • Amino Acid Sequence
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Drug Inverse Agonism*
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / chemistry
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Protein Conformation
  • Structure-Activity Relationship
  • User-Computer Interface


  • Acetamides
  • Nuclear Receptor Subfamily 1, Group F, Member 3