Discovering potent Onchocerca volvulus inhibitors from the ConMedNP library through virtual screening, MMGBSA, and molecular dynamics simulations

The biological activities of natural products from the ConMedNP library were investigated to identify suitable π-class (Ov-GST2) and σ-class (Ov-GST1) Glutathione S-transferases (GSTs) Onchocerca volvulus using virtual screening, MMGBSA rescoring, and molecular dynamics simulation. From an initial set of 3500 compounds (from the ConMedNP database), ADMET based filtering followed by tiered Glide docking (HTVS-SP-XP) and MMGBSA rescoring shortlisted 10 and 8 selected hit molecules against Ov-GST2 and Ov-GST1, respectively. Four representative compounds with the most favorable combined docking, MMGBSA, and ADMET profiles AN_UY_186_1 and AN_UY_088 for Ov-GST2, and BMC_00091 and SO_UY_018 for Ov-GST1 were retained for 200 ns molecular dynamics simulations. Trajectory analyses based on root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), protein ligand contacts, and intermolecular interactions identified AN_UY_088 (Ov-GST2) and SO_UY_018 (Ov-GST1) as the most stable complexes. These two homoisoflavanones, a subclass of flavonoids, are proposed as promising in silico leads against Ov-GST1/2; to our knowledge, no homoisoflavanone has previously been reported to target Ov-GST1, although our prior work has reported homoisoflavanones as Ov-GST2 binders using a different (South African) natural-product library. Experimental validation is required to confirm these computational predictions.