Identification of phytochemicals from genus Potentilla as estrogen receptor-α inhibitors through molecular docking, molecular dynamic simulation and DFT calculations.

Breast cancer is among the most prevalent causes of death in women worldwide. About 70-75% of these cancers are hormone-dependent, expressing estrogen receptors (ERs), mainly ER-α, making it an essential target for managing breast cancer. Potentilla genus has been traditionally used worldwide for its diverse biological activities, including antidiabetic, anti-inflammatory, antioxidant, etc. In the present study, phytochemicals isolated from various species of the Potentilla species were evaluated for their in silico ER-α inhibitory activity through molecular docking, molecular dynamic simulation, Density Functional Theory calculations and free energy calculations. Four hundred seventy-one molecules were used through ligand preparation and docked inside the generated grid on ER-α protein cavity and the standard drug tamoxifen. Fourteen molecules have shown better dock (-14.42 to -12.57 kcal/mol) scores than tamoxifen (-10.71 kcal/mol). Most of the molecules belong to the category of flavonoid glycosides. Molecules with good binding free energy (-78.81 to -12.94 kcal/mol) indicate stability inside the binding pocket. Further, based on dock score, pharmacokinetic parameters, and binding free energy, two hit molecules, 1 and 2, were selected for their molecular dynamic simulation, MM/PBSA and DFT calculations for assessing their stability and structural dynamics inside the binding cavity as well as their reactivity. Through MD simulation analysis, it was evaluated that Compound 1 could distort the protein to a greater extent. In contrast, compound 2 was stable throughout the simulation time of 150 ns and can be further explored in vitro and in vivo studies as ER-α inhibitors in breast cancer.