title: Molecular mechanism of interaction of mitocurcumin-1 with Akt1 and STAT3: an in silico approach.
abstract: The bioavailability of curcumin is the limiting factor for its effective use in anti-cancer therapy. Recently, we reported a novel approach to enhance the cellular uptake by conjugating curcumin with triphenyl phosphonium, named mitocurcumin-1. We found that such conjugation significantly increased the uptake of curcumin in various cancer cells and caused cancer cell death by inducing apoptosis by decreasing the phosphorylation of Akt1 (Thr308) and STAT3 (Tyr705). In this study, a molecular mechanistic model deciphering the regulation of phosphorylation of Akt1 and STAT3 by mitocurcumin-1 was investigated and compared with curcumin. The protein structures were obtained from protein data bank data base and protein-ligand interaction studies were performed with mitocurcumin-1 and curcumin. Docking interaction studies of mitocurcumin-1 with Akt1 and STAT3 active sites showed a strong binding affinity of -60.4107 Kcal/mol and -51.1734 Kcal/mol respectively, suggesting mitocurcumin-1 interacted with the residues at the active sites of phosphorylation of these molecules. Further, a Chi rotationary root mean square deviation of 1.468 angstroms and 3.965 angstroms at the active sites in Akt1 and STAT3, respectively indicated that changes in the conformation of protein structure at the active site resulted in the inhibition of phosphorylation of these molecules. To conclude, by using molecular modeling approaches for the first time, we demonstrated the inhibition of Akt1 and STAT3 phosphorylation by mitocurcumin-1.
authors.forename: Nagarjuna
authors.initials: N
authors.lastname: Vasagiri
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
mesh_terms: D003198:Computer Simulation; D003474:Curcumin / Q000378:metabolism*; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D008024:Ligands; D050796:STAT3 Transcription Factor; D051057:Proto-Oncogene Proteins c-akt; D003474:Curcumin