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

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. © 2023 Serbian Chemical Society. All rights reserved.

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

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 trans membrane 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.

Local guidelines for drug treatment of patients with covid-19

Objective. Until now, there have been no guidelines for the use of drugs in patients with COVID 19 in the Republic of Serbia that have been authorized and published in the professional or scientific literature, or on the official websites of the Ministry of Health or healthcare institutions. The aim of this paper is to present a local guideline for the use of drugs in patients with COVID 19 and the process of its development and adoption. Methods. The guideline proposal was prepared by a working group based on the results of a systematic research of the medical literature, and quality control of found publications from the category “clinical practice guidelines”. The proposal of the working group was considered and adopted at the sessions of the Drug / Therapeutics Committee and the Quality Assurance Committee of the University Clinical Centre Kragujevac. Results. The guideline's recommendations are based on the type of patient, and all have the same degree of recommendation and the same quality of evidence on which they are based. Patient types are formed according to the severity of the disease and the need for respiratory support, as well as according to the risk of secondary bacterial infection. Conclusion. The local guideline to the use of drugs in patients with COVID 19 was developed and adopted in a short period of time, primarily due to the need for its urgent use. A revision of this guide is planned after 6 months from the moment of adoption. © 2020, Serbian Medical Society. All rights reserved.