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.
