Drug repositioning to propose alternative modulators for glucocorticoid receptor through structure-based virtual screening

Abstract

Drug repositioning has recently become one of the widely used drug design approaches in proposing alternative compounds with potentially fewer side effects. In this study, structure-based pharmacophore modelling and docking was used to screen existing drug molecules to bring forward potential modulators for ligand-binding domain of human glucocorticoid receptor (hGR). There exist several drug molecules targeting hGR, yet their apparent side effects still persist. Our goal was to disclose new compounds via screening existing drug compounds to bring forward fast and explicit solutions. The so-called shared pharmacophore model was created using the most persistent pharmacophore features shared by several crystal structures of the receptor. The shared model was first used to screen a small database of 75 agonists and 300 antagonists/decoys, and exhibited a successful outcome in its ability to distinguish agonists from antagonists/decoys. Then, it was used to screen a database of over 5000 molecules composed of FDA-approved, worldwide used and investigational drug compounds. A total of 110 compounds satisfying the pharmacophore requirements were subjected to different docking experiments for further assessment of their binding ability. In the final hit list of 54 compounds which fulfilled all scoring criteria, 19 of them were nonsteroidal and when further investigated, each presented a unique scaffold with little structural resemblance to any known nonsteroidal GR modulators. Independent 100 ns long MD simulations conducted on three selected drug candidates in complex with hGR displayed stable conformations incorporating several hydrogen bonds common to all three compounds and the reference molecule dexamethasone.