Computational screening of Sophora flavescens phytochemicals as potential aromatase inhibitors: Molecular docking, ADMET, Network pharmacology, Molecular dynamics simulation, and DFT studies

Breast cancer is one of the most prominent types of cancers and a leading cause of fatality in women throughout the world. It also contributes to abnormal estrogen production. The enzyme aromatase (CYP19A1), which catalyzes estrogen biosynthesis, regulates hormone-dependent breast cancer. Therefore, it is used as a therapeutic target in breast cancer therapy. However, long-term usage of FDA-approved aromatase inhibitors, i.e., Letrozole and Anastrozole, in women demonstrates several adverse effects. Thus, the study was conducted to identify safer, natural alternatives using an integrated computational method. In the initial screening, more than 70 phytochemicals from the Sophora flavescens plant were docked against aromatase (PDB ID: 3EQM) using PyRx. Though Artocarpin SF02 showed the highest binding affinity among these phytochemicals (-10.1 kcal/mol), it had the highest toxicity to the immune system and the lowest LD50 value compared to SF03. So SF04 Vogelin E , having a binding affinity of (-9.3Kcal/mol), followed by its good pharmacokinetic & toxicity profile. Network pharmacology revealed that it interacts with targets of interest, including CYP19A1, ESR1, and EGFR, which regulate estrogen biosynthesis, as well as PI3K-Akt and MAPK signaling pathways, in breast cancer development. The stability of the aromatase-Vogelin E complex was confirmed by performing MD simulations with GROMACS 2022.4 using the CHARMM36 force field and TIP3P water model, which predicted stable complex formation over the 100ns trajectory. To further validate the chemical stability and electronic reactivity of the selected compound, DFT calculations were performed using Gaussian 09 with the B3LYP/6-31G basis set. These findings suggest that a flavonoid-based derivative, Vogelin E, derived from the Sophora flavescens plant may be a highly effective, safe, and natural aromatase inhibitor. This research offers a good prospect for in vitro and in vivo research to develop alternative therapies to be used in hormone-dependent breast cancer. • Vogelin E was discovered as a novel natural aromatase inhibitor. • A comprehensive computational approach (molecular docking, ADMET, network pharmacology, molecular dynamics, and DFT) was employed. • The stability of the complex was validated through 100 ns molecular dynamics simulations. • Compared to FDA-approved drugs, it exhibits low toxicity and superior pharmacokinetic properties. • A safe, flavonoid-based candidate drug for the treatment of breast cancer is proposed.