Structure-based virtual screening, molecular docking, molecular dynamics simulation and MM/PBSA calculations towards identification of steroidal and non-steroidal selective glucocorticoid receptor modulators

Glucocorticoids have been used in the treatment of many diseases including inflammatory and autoimmune diseases. Despite the wide therapeutic effects of synthetic glucocorticoids, the use of these compounds has been limited due to side effects such as osteoporosis, immunodeficiency, and hyperglycaemia. To this end, extensive studies have been performed to discover new glucocorticoid modulators with the aim of increasing affinity for the receptor and thus less side effects. In the present work, structure-based virtual screening was used for the identification of novel potent compounds with glucocorticoid effects. The molecules derived from ZINC database were screened on account of structural similarity with some glucocorticoid agonists as the template. Subsequently, molecular docking was performed on 200 selected compounds to obtain the best steroidal and non-steroidal conformations. Three compounds, namely ZINC_000002083318, ZINC_000253697499 and ZINC_000003845653, were selected with the binding energies of -11.5, -10.5, and -9.5 kcal/mol, respectively. Molecular dynamic simulations on superior structures were accomplished with the glucocorticoid receptor. Additionally, root mean square deviations, root mean square fluctuation, radius of gyration, hydrogen bonds, and binding-free energy analysis showed the binding stability of the proposed compounds compared to budesonide as an approved drug. The results demonstrated that all the compounds had suitable binding stability compared to budesonide, while ZINC_000002083318 showed a tighter binding energy compared to the other compounds. Communicated by Ramaswamy H. Sarma