Systematic In-silico Analysis of Fisetin-Proteins Interactions Revealing the PTGS2 as a Potential Therapeutic Target

Abstract Fisetin is a nutraceutical that provides many health benefits, including anticancer, anti-aging, anti-inflammatory, and antidiabetic activities. The present study revealed the molecular mechanism of fisetin through the PCI and PPI interactions network analysis. The optimized geometry of fisetin, free energy, and polar response were estimated using Gaussian 9.0. AutoDock Vina was used to perform the molecular docking between fisetin and the STITCH-identified proteins. MD simulations were also performed by GROMACS for 100 ns to validate the Docking results and analyze the stability and dynamic behavior of the fisetin-PTGS2 complex under the physiological condition. This study identified 110 proteins by PCI and PPI, and also obtained 15 crucial proteins that regulate autophagy, cell growth, protein-serine kinase activity, cytokine activity, and different pathways. Docking studies revealed that fisetin strongly interacted with PTGS2 and ADAM9 with the binding affinities of -9.4 and -8.9 kcal/mol, respectively. DFT calculations and MD studies reveal that fisetin has a strong electronic reactivity and can efficiently interact with PTGS2, leading to the potential use of this compound as an antineoplastic/oxidative stress therapeutic agent. Overall, these findings describe the molecular basis for fisetin's multiple beneficial effects and suggest its further development into a health-promoting therapeutic agent. Keywords Fisetin, Network pharmacology, DFT calculation, MD simulation