Integrated Network Pharmacology, Docking and ADMET Profiling of Fluoro-Aminopyrimidines as Anti-Prostate Cancer Agents

Abstract

Prostate cancer is the second most frequent cancer in men worldwide. It has an age-adjusted incidence rate of 29.4 per 100,000 populations and produces around 14.2% of new cancer cases in men. Fluoro-aminopyrimidine scaffold, exhibit the pharmacological activities such as anticancer, antiviral and antimicrobial properties. Totally 2746 compounds were retrieved from PubChem database. SwissADME and pkCSM web servers were used to estimate the compounds physicochemical, pharmacokinetic, metabolic and toxicological profiles. OSIRIS Property Explorer was used to estimate the drug score. The compounds which are having good pharmacokinetic and less toxic profile were selected for further screening. Network pharmacology and gene ontology analysis was utilised to predict the top targets involved in prostate cancer. Molecular docking was performed using Mz-Dock with Autodock Vina mode and visualised by PyMol. A total of 11 compounds were finalized and network was constructed using cytohubba plugin cytoscape. Top 6 targets were identified using Cytohubba, among them top three targets were selected namely, PIK3R1, PIK3CA and EP300 based on the KEGG Pathway enrichment analysis. Molecular docking results revealed that two compounds namely, 4-[3-[2-Amino-6-(5-chloro-2-fluoro-3-methylphenyl)pyrimidin-4-yl]propyl]benzamide and 5-fluoro-2-[[(1R)-1-(4-oxo-2-phenyl-1,9a dihydropyrido[1,2a]pyrimidin-9-yl)ethyl]amino] benzoic acid were found to be significantly active against the selected targets with good binding energies and interactions, according to various in silico studies and drug scores. Thus, these compounds can be used as chemotherapeutic agents for the treatment of prostate cancer. However, further in vitro and in vivo studies are warranted.