Molecular Design, Docking and Dynamic Studies of Novel B, C-Ring Truncated Deguelin Derivatives with Cyclin D1 and Cyclin E

The overexpression of cyclin D1 and cyclin E due to their oncogenic potential and amplification has been associated with a higher mortality rate in many cancer. The deguelin is a natural compound, has shown promising anti-cancer activity by directly binding cyclin D1 and Cyclin E and thus suppressing its function. The C7a atom position of deguelin structure, contain proton which generates stabilized radical, as a result, decomposed deguelin reduces its structural stability and significantly decreases its biological activity. To develop deguelin derivatives with the reduced potential side effect, series of B, C-ring truncated derivates were investigated as cyclin D1 and cyclin E inhibitor. R-group based enumeration implemented in the deguelin scaffold using the R-group enumeration module of Schrodinger. Drug-Like filters like, REOS and PAIN’s series was applied on the enumerated compound library to remove compounds containing reactive functional groups. The resulted drug-like compounds were subjected to ligand preparation and energy minimization using the OPLS3e force field. Further, screened compounds were docked within the ligand-binding cavity of cyclin D1 and cyclin E crystal structure, using Glide SP protocol to obtain docking poses. The best 100 poses from different enumeration were selected for the XP docking protocol to reveal the XP descriptors, which describes each atom's contribution concerning rewards and penalties for docking energy. Enrichment Calculations were done using Schrodinger software, with 1000 decoy compounds (from DUD.E database) and 60 Compounds (XP best poses) along with Deguelin and docking was carried out by XP protocol. The results of enrichment calculations suggesting that docking protocol is validated because Receiver Operating Characteristic (ROC) curve shows R2= 0.92 for Cyclin D1 and R2 = 0.87 for cyclin E. Also, Hierarchical Clustering was carried out using best 10 poses from different enumeration along with Deguelin compound, to know the structural diversity of enumerated compounds. Besides, we explored molecular dynamics simulation to probe the binding stability of deguelin and its derivatives within the binding cavity of cyclin D1 and cyclin E structure which is associated with the cyclin D1 and cyclin E inhibitory mechanism.