Identification of novel agonists and antagonists of the ecdysone receptor by virtual screening

J Mol Graph Model. 2018 May:81:77-85. doi: 10.1016/j.jmgm.2018.02.016. Epub 2018 Mar 2.

Abstract

Insect growth is regulated by the steroid hormone 20-hydroxyecdysone (20E), which works via the ecdysone receptor (EcR). To identify biologically active and novel ecdysone agonists/antagonists, ligand/structure-based virtual screening combined with pharmacophore modeling and molecular docking was performed to identify novel nonsteroidal lead compounds. Nine molecules were screened and selected for an in vitro cell-based reporter bioassay. The results showed that VS-006 and VS-009 exhibited antagonistic activity in S2 cells, whereas only VS-006 exhibited antagonistic activity in Bm5 cells. Molecular dynamic simulation of VS-006 complexed with the ligand binding domain of EcR validated the binding stability of VS-006 and highlighted the key residues for further lead optimization.

Keywords: Agonists; Antagonists; Ecdysone receptor; Molecular docking; Molecular dynamic simulation; Virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Discovery* / methods
  • Gene Expression Regulation / drug effects
  • Genes, Reporter
  • Ligands
  • Molecular Conformation
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Protein Binding
  • Receptors, Steroid / agonists
  • Receptors, Steroid / antagonists & inhibitors
  • Receptors, Steroid / chemistry*
  • Small Molecule Libraries
  • Structure-Activity Relationship

Substances

  • Ligands
  • Receptors, Steroid
  • Small Molecule Libraries
  • ecdysone receptor