Virtual Screening of Phytochemicals From Medicinal Plants as Promising PDE5 Inhibitors Against Erectile Dysfunction

Area of Science:

• Computational chemistry and pharmacology
• Natural product drug discovery

Background:

• Erectile dysfunction (ED) is a prevalent condition with significant impact on quality of life.
• Current ED treatments have limitations, necessitating the search for novel therapeutic agents.
• Medicinal plants represent a rich source of bioactive compounds with therapeutic potential.

Purpose of the Study:

• To identify and evaluate bioactive phytochemicals from Algerian medicinal plants as potential phosphodiesterase-5 (PDE5) inhibitors.
• To assess the in silico drug-likeness, toxicity, and binding affinities of these compounds against PDE5.
• To develop a quantitative structure-activity relationship (QSAR) model for predicting PDE5 inhibitory activity.

Main Methods:

• Screening of 76 compounds from 48 Algerian plant species for drug-likeness (SwissADME) and toxicity.
• Molecular docking simulations to predict binding affinities of compounds to the PDE5 active site.
• Molecular dynamics simulations and MM-GBSA analysis for assessing binding stability and free energy.
• Development of a QSAR model using Random Forest regression based on molecular descriptors and docking results.

Main Results:

• 72% of screened compounds exhibited favorable oral bioavailability (Lipinski's Rule of Five), and 29 were predicted as non-toxic.
• Ellagic acid, rosmarinic acid, salvinorin A, and catechin demonstrated strong binding affinities to PDE5.
• Molecular dynamics and MM-GBSA confirmed stable interactions and favorable binding free energies for rosmarinic acid and salvinorin A.
• The QSAR model achieved high predictive performance (R²train=0.91, R²CV=0.87), identifying LogP, molecular weight, and TPSA as key determinants.

Conclusions:

• Phytochemicals, particularly catechin and related compounds, are promising natural inhibitors of PDE5.
• These findings support the further preclinical investigation of these natural compounds as potential therapies for ED.
• The identified compounds offer a potential for developing safer and more affordable ED treatments.