In silico study of aminothiazole, benzohydrazide, namoline, piridine, and parnate derivatives as Jumonji domain histone lysine demethylase (KDM1A, KDM4A, KDM4C, KDM4E, AND KDM5B) inhibitors in prostate cancer

Abstract

Background: Prostate cancer is the second most common type of cancer in men. The histone lysine demethylase enzyme is believed to be one of the genetic factors that cause prostate cancer. Based on in vivo testing, a group of compounds from the aminothiazole, benzohydrazide, pyridine, namoline, and parnate classes have been experimentally proven to be inhibitors of the histone lysine demethylase enzyme. Objective: This study aimed to investigate the interaction of 20 compounds consisting of aminothiazole, benzohydrazide, pyridine, namoline, and parnate derivatives with histone lysine demethylase enzymes (KDM1A, KDM4A, KDM4C, KDM4E, and KDM5B) in silico. Method: Molecular docking was performed using Autodock Tools v.4.2.3 to obtain the affinity of test compounds against the target molecule. This was followed by molecular dynamics (MD) simulation of some test compounds with the lowest inhibition constant using Gromacs software. Toxicity prediction was conducted to predict the safety of the test compounds. Result: The docking results revealed the top five compounds for each receptor with the lowest inhibition constant and free binding energy value (∆G), suggesting the best affinity to histone lysine demethylase enzymes. The results from MD showed that the compounds with the codes aminothiazole, pyridine, parnate 1, parnate 2, and parnate 5 were stable when bound to the KDM1A receptor. The toxicity test results also indicated that the test compounds were safe and had a low health risk, as they were neither genotoxic nor non-genotoxic carcinogens. Conclusion: Based on the research results, it can be concluded that compounds with the codes aminothiazole, pyridine, parnate 1, parnate 2, and parnate 5 can serve as inhibitors of histone lysine demethylase enzymes on the KDM1A receptor and are stable when bound to the receptor.