In silico prediction of cinnamaldehyde on the PI3K/AKT pathway activator of anti-apoptotic potential

Context: The dysregulation of the phosphoinositide 3-kinase protein kinase B (PI3K/AKT) signaling pathway has been associated with diabetes and its complications. Cinnamaldehyde (CA) can potentially inhibit diabetes complications through its pleiotropic effects, including anti-inflammatory, anti-oxidative, and anti-apoptosis. However, whether these effects are related to PI3K/AKT pathway modulation is unknown. Aims: To evaluate the interaction of cinnamaldehyde with proteins involved in the PI3K/AKT pathway. Methods: This study involved pharmacokinetic analysis, molecular docking, and molecular dynamics. The ligand used was cinnamaldehyde, and the proteins were eight crystal structures of proteins related to the PI3K/AKT pathway. For comparison purposes, we selected compound UCL-TRO-1938 (PI3K activator), baicalin (AKT activator), and bisperoxovanadium (PTEN inhibitor) as control ligands. Results: The results of this study indicated that CA has the potential to be an oral-drug candidate as it fulfills all Lipinski criteria and shows good cell membrane permeability. Molecular docking showed that CA exhibited good binding affinities toward target proteins. CA showed stronger binding affinity to the p110α subunit of PI3K (-6.4 vs. -6.3 kcal/mol) and PTEN (-5.8 vs. -5.0 kcal/mol) compared to the control ligand. CA also interacts with similar amino acid residues compared to control ligands. A molecular dynamic study revealed that CA and control ligands-protein complexes have similar stability with few conformational alterations in several amino acid residues. Conclusions: CA has the potential to be a drug candidate to ameliorate diabetes complications by up-regulating the PI3K/AKT pathway. Further experimental study is required to ascertain its efficacy.