Molecular docking analysis of anti-cancer activity of Flueggea leucopyrus phytocompounds as androgen receptor antagonists in prostate cancer

Abstract

Prostate cancer affects over 1.4 million men globally and is the fifth most prevalent cause of cancer-related deaths. It primarily occurs due to the overstimulation of the androgen receptor, and although existing treatments have serious adverse effects, plant-derived compounds are being investigated as alternatives, including those from the leaves of the Sri Lankan Katupila (Flueggea leucopyrus) plant, as potential anticancer agents. The impact of Katupila phytocompounds on prostate cancer remains unexplored, even though they have demonstrated anticancer potential in ovarian and breast carcinomas. Therefore, this research study aimed to computationally investigate the anticancer effects of five main phytochemicals of the Katupila plant: bergenin, securinol-A, stigmasterol, dl-α-tocopherol, and ursodeoxycholic acid by evaluating their binding energies, non-covalent interactions, and inhibition constants with the prostate cancer-related target, androgen receptor protein (2AM9). Firstly, density functional theory (DFT) calculations were performed to geometrically optimise these five phytochemicals, which were obtained from the PubChem database. AutoDock 4.2.6 software was used to carry out molecular docking studies after the protein crystal structure of the androgen receptor was retrieved from the Protein Data Bank. Binding energies and inhibition constants were subsequently analysed, with enzalutamide serving as a reference compound—a currently FDAapproved anticancer drug for prostate cancer treatment. The results demonstrated that stigmasterol had the highest binding affinity to the androgen receptor (-10.12 kcal/mol) with an inhibition constant of 0.038 μM, exceeding that of the reference drug (-8.05 kcal/mol; 1.260 μM). Binding affinities for bergenin, securinol-A, di-α-tocopherol, and ursodeoxycholic acid were –6.28, –8.20, –7.10, and –9.14 kcal/mol, respectively; the affinities for securinol-A and ursodeoxycholic acid were greater than those for the reference. According to computational chemistry standards, binding affinity values ranging from -6.0 to -11.0 kcal/mol are considered favorable. Stigmasterol exhibited non-covalent interactions, including H-bonds with GLY 919 and hydrophobic interactions with ILE 816, ILE 914, and LYS 912, as well as TYR 915. The binding affinity order was determined as follows: bergenin <di-α-tocopherol < securinol-A < ursodeoxycholic acid < stigmasterol. These investigations provide computational support for the hypothesis that Flueggea leucopyrus possesses anticancer potential against prostate cancer by inhibiting the overexpression of the androgen receptor. Moreover, these findings suggest that the investigated phytocompounds represent promising candidates with significant anticancer potential against prostate cancer, and deserve further experimental validation.