In-silico identification of novel inhibitors of human androgen receptors and prostrate-specific membrane antigen: a comprehensive target-based molecular docking, molecular dynamics simulation, and ADME-toxicity studies.

Prostate cancer (PC) remains a deadly disease that requires urgent attention. It's the second most frequent cancer type that affects men globally, with over 1.4 million cases and 358,989 deaths recorded so far. Despite the several available treatment options ranging from surgery (prostatectomy) to chemo- and radiation therapy for PC patients, associated side effects such as risk of excessive bleeding after treatment, erectile dysfunction, risk of infertility, and incontinence, among others, necessitate the need for a safer and highly effective anti-prostate cancer medication, especially from natural sources. Thus, the current study examines eighty-three isolated compounds from Rauwolfia vomitoria as potential anti-prostate cancer medication using a computer-aided drug design (CADD) approach. The choice of Rauwolfia vomitoria is due to its reported medicinal value. Researchers have explored this utility plant to treat numerous health challenges, including cancer. Thus, the isolated compounds (ligands) were docked against prostate cancer drug targets with PDB IDs 1XOW and 2XEI using the Pyrx docking tool. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the selected ligands were analyzed using the admetSAR3.0 tool. In contrast, SwissADME was used to analyze the drug-likeness and bioavailability of the selected ligands, including other physicochemical properties, binding modes, and molecular interactions. The molecular dynamics simulation of the identified lead and PC standard drug was carried out using GROMACS 2018. 3 software, while trajectories were analyzed using GROMACS modules, and all plots were done using the Xmgrace tool. The result of all these operations identified L4 (cholesterol-3-13C) and L80 (stigmasterol) as novel lead compounds against the two prostate cancer drug targets (1XOW and 2XEI), which have not been reported earlier to the best of our knowledge. The binding affinities of both leads are (- 8.2 kcal/mol and - 9.8 kcal/mol for L4 against 1XOW and 2XEI, respectively) and (- 9.0 kcal/mol and - 9.1 kcal/mol for L80 against 1XOW and 2XEI, respectively). The identified lead possessed excellent ADMET properties, bioactivities, and drug-likeness and interacted effectively with the target sites. The molecular dynamics simulation studies of the identified ligand also confirmed their stability in the active site of the drug targets. Therefore, these leads could be optimized and developed towards the development of novel therapeutic agents against prostate cancer.