Screening the binding affinity of bile acid derivatives for the glucocorticoid receptor ligand-binding domain

Abstract

The necessity of anti-inflammatory drugs such as glucocorticoids has been evident during the COVID-19 pandemic. Glucocorticoids, are the standard therapy for the treatment of moderate and severe COVID-19 patients. However, serious side effects limit the use of these drugs, and anti-inflammatory drugs with better pharmacological properties are urgently required. Bile acids are of interest, because of their anti-inflammatory and immunomodulatory properties, facilitated through an unclear mechanism involving transmembrane and nuclear receptors. In this work, we screened the binding activity of a number of bile acid derivatives, for the ligand-binding domain of glucocorticoid receptor (GR-LBD), the most important receptor for anti-inflammatory processes. Tested compounds include oximes, lactones, lactams, tetrazoles, dienones, C-24 alcohols and cholic acid amides. Cholic acid oxime, deoxycholic acid dienone, 3-keto-24-cholic alcohol and cholic acid amide showed best binding affinities for GR-LBD among tested compounds. The in silico molecular docking explanation is provided. SAR analysis showed that expansion of B and C steroid rings or attachment of heterocycle to C ring is not beneficial for binding; side chain should contain hydrogen donor group; the GR-LBD tolerate well different functionalities on C-3 position. These results provide valuable information toward synthesis of the new glucocorticoids based on bile acids.

Keywords

• organic synthesis
• docking studies
• molecular modelling