In silico molecular docking, molecular dynamics, and ADMET analysis of metabolites from Strychnos cocculoides as potential therapeutics for erectile dysfunction: a comparative study with sildenafil

This study investigated the inhibitory potential, pharmacokinetic behavior, and toxicity profiles of selected bioactive metabolites from Strychnos cocculoides as natural analogs of Sildenafil for the management of erectile dysfunction. The metabolites were tentatively identified using UHPLC-MS/MS and MZmine 4.2 molecular networking tool. Eight metabolites, including the reference drug Sildenafil (L8), were subjected to in silico molecular docking against phosphodiesterase type 5 (PDE5; PDB ID: 2H42), and phosphodiesterase type 6 (PDE6; PDB: 5ML2) followed by MM/GBSA binding free energy evaluation. Pharmacokinetic (ADMET) and toxicity properties were predicted using SwissADME and Protox-II tools to assess drug-likeness, bioavailability, and organ-specific safety. Metabolote L4 (3 S,6R,6aS,7 S)-6,6a,7,8-tetrahydroxy-3-methyl-3,4,5,6,7,12a-hexahydro-2 H-benzoaanthracene-1,12-dione exhibited the strongest binding affinity toward the PDE5 receptor (–8.22 kcal/mol) and a favorable MM/GBSA binding free energy (–46.3 kcal/mol), comparable to the reference drug sildenafil. ADMET profiling revealed high gastrointestinal absorption, absence of CYP enzyme inhibition, and optimal lipophilicity. Toxicity predictions classified L4 as moderately safe (LD₅₀ = 220 mg/kg; toxicity Class 3), with low probabilities of carcinogenicity and mutagenicity. In contrast, metabolite L6 (hydrocortisone) exhibited the strongest binding affinity against the PDE6 receptor (–9.45 kcal/mol) and a favorable MM/GBSA binding free energy (–49.50 kcal/mol), also comparable to sildenafil. ADMET predictions similarly indicated high gastrointestinal absorption, no CYP inhibition liability, and optimal lipophilicity. Toxicological assessment categorized L6 as safe (LD₅₀ = 5000 mg/kg; toxicity Class 5), with low mutagenic potential. L4 exhibits strong inhibitory activity against PDE5, while L6 shows potent inhibition of PDE6. Both metabolites display favorable pharmacokinetic characteristics and acceptable safety profiles, supporting their potential as natural and safer analogs of sildenafil. Nonetheless, further experimental studies are required to validate their therapeutic effectiveness and assess their clinical applicability.