Deciphering the role of zingiber officinale phytochemicals for the treatment of prostate cancer: Interactions of phytochemicals with androgen receptor prostate cancer mutant H874Y ligand binding domain.

[BACKGROUND] The mutations in the Androgen Receptor (AR) known as H874Y in prostate cancer greatly influence cellular signaling and execute the cell proliferation. Phytochemicals of ginger (Zingiber officinale) extracted from methanol extract were investigated through multiple servers to identify the ADMET properties.

[METHODS] Our key considerations were on Gingerol and Gingerenone and their bindings with AR Prostate Cancer Mutant H874Y. Moreover, the molecular docking simulations, molecular dynamics, and simulations were executed to determine the key insight into the binding affinity, stability, and motions of the Prostate Cancer Mutant H874Y Ligand Binding Domain. In-vitro study was performed to evaluate the cytotoxicity of Zingiber officinale against 3 cell lines A549, MCF-7, and PC-3. Furthermore, cell nuclear morphology was analyzed using DAPI staining.

[RESULTS] The ADMET investigations revealed positive results concerning absorption, distribution, metabolism, and excretion with no signs of toxicity commenced and better binding affinity for Gingerol and Gingerenone-A. The molecular dynamics simulations were employed for the Prostate Cancer Mutant H874Y Ligand Binding Domain complexed Gingernone-A and Gingerol over 100 ns to identify the atomistic motions and stability of the desired ligands. The MD Simulations revealed that Gingernone-A was found stable, suggesting more consistent bindings and stability with higher hydrogen bond contacts during simulations. Moreover, the Gingerol was found equally stable to Gingernone-A confirmed by root mean square deviations (RMSD) which reflects the dynamic nature of the Gingerol. Furthermore, other parameters such as RMSF, and compactness were found within permissible limits. To validate the molecular docking simulations as well as molecular dynamics simulations the free energy was calculated from the whole trajectory obtained from the MD Simulations using the MM-PBSA method. Both Gingerol and Gingernone-A were found to be better modulators of the H874Y mutated ligand-binding domain with free binding energy for Gingerol -189.351 ± 1.272kJ/mol and Gingernone-A -322.881 ± 1.665 kJ/mol. Such negative binding energies provide an understanding of the binding nature of ligands with the template target. Moreover, the Gingerol with AR Prostate Cancer Ligand Binding Domain binding showed free binding energy -292.984 ± 2.673 kJ/mol. These negative binding energies illustrate the ligands' binding strengths. The results of in-vitro study showed good anticancer potential in methanol extract of Zingiber officinale against A549, MCF-7, and PC-3 cell lines with IC values of 464, 542, and 604 μg/mL respectively. The results of DAPI staining were showed remarkable changes in cell nuclear morphology.

[CONCLUSIONS] The results of current in-siico and in-vitro studies are important for gaining an understanding of the mechanisms of how the Zingiber officinale phytochemicals bind to the H874Y mutated ligand binding domain, which is important for the development of targeted therapy against Prostate Cancer Mutant H874Y.