Molecular docking and dynamic simulation approach to decipher steroidal sapogenins (genus Trillium) derived agonists for glucocorticoid receptor

Steroidal sapogenins (SS) are structural analogues of steroidal drugs, which are frequently used for the treatment of several diseases including reproductive, malignancies, neurological, and inflammation-related diseases. The glucocorticoid receptor (GR) is a nuclear receptor that regulates development, metabolism, and inflammation, in response to steroidal ligands. Therefore, GR is considered as a potential therapeutic target for steroidal agents to the treatment of inflammation-related diseases. We hypothesized that SS may act as an agonist for GR due to structural similarity with corticosteroids. In this study, we carried out in silico screening of various SS from the genus Trillium to check their potential as an agonist for GR. Our data suggest that out of 42 SS, only 7 molecules have interacted with GR. However, molecular mechanics with generalized Born and surface area (MM-GBSA) analysis revealed that only two SS (SS 38 and SS 39) molecules bind favorably to GR. Among these, SS 38 (docking score: -9.722 Kcal/mol and MM-GBSA Delta G(bind): -50.192 Kcal/mol) and SS 39 (docking score: -11.20 Kcal/mol and MM-GBSA Delta G(bind): -58.937 Kcal/mol) have best docking and MM-GBSA scores. Molecular dynamics (MD) simulation studies of SS 38, SS 39, and dexamethasone-GR complex revealed that both SS shows hydrogen bonding and hydrophobic interaction with GR over the 120 ns simulation with mild fluctuations. The current study suggests that SS 38 and SS 39 may be further explored as a potential agonist to treat several disease conditions mediated by GR.

Automated summary

In this study, we conducted in silico screening of steroidal sapogenins (SS) from the genus Trillium to identify potential agonists for the glucocorticoid receptor (GR). Our findings suggest that two SS molecules (SS 38 and SS 39) exhibit favorable binding to GR, as revealed by docking scores and MM-GBSA analysis. Molecular dynamics simulation studies further confirmed stable interactions between these SS molecules and GR. These findings indicate that SS 38 and SS 39 may have potential as agonists for GR-mediated diseases.