High throughput virtual screening of phosphodiesterase type-5 (PDE-5) inhibitors against erectile dysfunction from Saussurea lappa roots: An integrated approach utilizing GC-MS, machine learning, docking, molecular dynamics, and DFT based analysis

Erectile dysfunction (ED) is a widespread male sexual health issue that becomes more common with advancing age. In the decade preceding, there has been a notable rise in the occurrence of ED worldwide, with a special emphasis on developing nations like Africa, Asia, and South America. The fundamental process of ED generally involves the dysfunction of the nitric oxide-cGMP pathway, which is controlled by the enzyme phosphodiesterases type 5 (PDE5). While PDE5 inhibitors such as sildenafil have shown effectiveness in treating ED, they often come with unwanted side effects and contraindications, creating a need for alternative therapies. The present work explores the potential of two phytochemicals, Chrysophanol and Saussurea lactone, extracted from Saussurea lappa, as novel PDE5 inhibitors for treatment for ED. After 60 phytochemicals have been identified by gas chromatography-mass spectrometry (GC-MS) learning, they were evaluated in silico. Using a multilayer perceptron (MLP) classifier having a true positive rate of 0.965 and a highest ROC area of.970, a machine learning model was initially developed. Further, 10 active phytochemicals screened by the model underwent ADMET profiling assessment before molecular docking studies with PDE5. All identified phytochemicals demonstrated binding energy scores between -9.4 and -6.8 kcal/mol, with Chrysophanol and Saussurea lactone showing particularly promising binding characteristics. Subsequent 100-nanosecond molecular dynamics simulations revealed that these two compounds exhibited greater stability compared to sildenafil, The findings reveal that the solvent accessible surface area (SASA) values range from 155.37 f 2.30 nm2 to 162.14 f 2.14 nm2, the radius of gyration readings within 1.61 f 0.03 nm and 1.94 f 0.05 nm, and the root mean square deviation (RMSD) readings between 0.23 f 0.01 nm and 0.20 f 0.01 nm. The hit compounds also showed promising results during PCA, hydrogen binding and FEL analysis. Electronic properties of the compounds and chemical reactivity of the compounds were also analyzed yielded with HOMO-LUMO energy gaps ranging from -3.4 eV to -6.6 eV. Further, in vitro and in vivo analysis are also suggested for future drug development to check effectiveness and safety profile of the screened compounds for proving their appropriateness for clinical applications during erectile dysfunction treatments.