Natural phosphodiesterase 5 (PDE5) inhibitors: a computational approach

Nat Prod Res. 2021 May;35(10):1648-1653. doi: 10.1080/14786419.2019.1619726. Epub 2019 May 29.


In 1998, sildenafil was marketed as the first FDA-approved oral drug for the treatment of erectile dysfunction (ED). During the last two decades, the commercialization of other synthetic phosphodiesterase 5 (PDE5) inhibitors has been paralleled by the rise of remedies based on natural molecules from different chemical classes (flavonoids, polyphenols and alkaloids in general). In this work, a set of in silico tools were applied to study a panel of 30 natural compounds claimed to be effective against ED in the scientific literature or in folk medicine. First, pharmacokinetic properties were analysed to exclude the compounds lacking in specific drug-like features. Estimated binding energy for PDE5 and selectivity towards other PDE isoforms were then considered to highlight some promising molecules. Finally, a detailed structural investigation of the interaction pattern with PDE in comparison with sildenafil was conducted for the best performing compound of the set.

Keywords: PDE5; docking; erectile dysfunction; flavonoids; sildenafil.

MeSH terms

  • Binding Sites
  • Biological Products / pharmacology
  • Biological Products / therapeutic use
  • Computer Simulation
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / chemistry
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
  • Drug Evaluation, Preclinical / methods
  • Erectile Dysfunction / drug therapy
  • Humans
  • Male
  • Medicine, Traditional
  • Phosphodiesterase 5 Inhibitors / chemistry*
  • Phosphodiesterase 5 Inhibitors / pharmacokinetics
  • Phosphodiesterase 5 Inhibitors / pharmacology*
  • Phosphodiesterase 5 Inhibitors / therapeutic use
  • Sildenafil Citrate / pharmacology


  • Biological Products
  • Phosphodiesterase 5 Inhibitors
  • Sildenafil Citrate
  • Cyclic Nucleotide Phosphodiesterases, Type 5