Identification of Potent Inhibitors of Akt Kinases inhibitors from natural sources for Therapeutic Targeting of Oral Squamous Cell Carcinoma

Background Plant-based natural compounds are effective cancer cell proliferation inhibitors. Consequently, the quest for these compounds for the treatment of cancer has become increasingly competitive and has opened up new avenues for drug development. The current investigation extensively addressed the virtual screening and structure-based prediction of compounds derived from natural products against Protein kinase B-alpha (PKBα, also known as Ak/4GV1). Material and Methods In this study, we conducted a thorough screening of putative PKBα inhibitors from a natural products library, and subsequently performed molecular modeling. Results This research identified Irciniastatin B, Irciniastatin A, Pseudoceroxime D, (1'S)-7-chloroaverantin as the top four potential PKBα inhibitors from the library of natural products, whose Glide docking scores range from -10.689 to -7.567 kcal/mol. The RMSD and RMSF analysis reveals that all four ligands remain stable and maintain their interaction throughout the simulation time. The MM/GBSA (ranging from -37.26 to -51.02 kcal/mol) predicted binding affinities are in strong co-relation with that of the docking score, which not only supports the docking results but also suggests that Irciniastatin B exhibits superior binding affinity towards PKBα amongst all four studied compounds. Moreover, the interaction analysis also indicates that Irciniastatin B establishes at least 12 interactions with the neighbouring residues whereas, Irciniastatin A, Pseudoceroxime D, and (1'S)-7-chloroaverantin compounds were able to establish 8-9 interactions in the binding cavity of PKBα. ADMET assessment of the selected compounds was also noted to be within acceptable ranges. Conclusion Keeping in view these findings, Irciniastatin B might be a promising candidate for drug discovery against PKBα inhibitors.