In-Silico Evaluation of FDA-Approved Drugs as PDE5 Inhibitors for Treatment of Hepatocellular Cancer

Hepatocellular carcinoma (HCC) is a predominant cause of cancer-associated mortality, characterized by restricted treatment alternatives and unfavorable prognosis. Phosphodiesterase type 5 (PDE5) plays an important role in cancer development; thus, repurposing FDA-approved PDE5 inhibitors for HCC therapy, focusing on essential pathways like apoptosis and angiogenesis, would provide safe and effective treatment alternatives. This work seeks to assess the potential of FDA-approved drugs from the DrugBank library as PDE5 inhibitors against HCC-related targets by in-silico methods, thus identifying a safe and effective PDE5 inhibitor for HCC therapy. Molecular docking was conducted to evaluate the binding affinities of PDE5 inhibitors. Furthermore, ADMET profiling was performed utilizing web servers such as SwissADME, pkCSM, and ProTox to identify candidates possessing ideal drug-like characteristics. Molecular dynamics simulation was then utilized to confirm the stability and interactions of the highest-performing compounds. The best docked stable drug candidate was then docked with critical oncogenic proteins (PDE5, VEGFR-2, caspase-9, and caspase-7). Metabolite 4-hydroxy Nebivolol (DBMET02738) and Nabumetone ( ) had high docking scores of -12.781 and -12.573 kcal/mol with PDE5 and VEGFR-2 or Caspase-9, with excellent ADMET profiles and stability in the molecular dynamics simulation. Their binding affinities surpassed well-established drugs for HCC, such as Sorafenib or Regorafenib. Nebivolol metabolite (DBMET02738) and Nabumetone metabolite (DBMET02532) exhibit potential as repurposed PDE5 inhibitors for hepatocellular carcinoma treatment, according to their robust protein-binding affinities, advantageous pharmacokinetics, and minimal toxicity profiles.