Molecular docking and dynamic simulation approach to decipher steroidal sapogenins (genus <i>Trillium</i>) 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 <i>in silico</i> screening of various SS from the genus <i>Trillium</i> 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 <b>38</b> and SS <b>39</b>) molecules bind favorably to GR. Among these, SS <b>38</b> (docking score: –9.722 Kcal/mol and MM-GBSA ΔG_bind: –50.192 Kcal/mol) and SS <b>39</b> (docking score: –11.20 Kcal/mol and MM-GBSA ΔG_bind: –58.937 Kcal/mol) have best docking and MM-GBSA scores. Molecular dynamics (MD) simulation studies of SS <b>38</b>, SS <b>39</b>, 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 <b>38</b> and SS <b>39</b> may be further explored as a potential agonist to treat several disease conditions mediated by GR. Communicated by Ramaswamy H. Sarma