Identification of key pharmacophore feature motifs from the potent leads of the major antioxidant enzymes of W. bancrofti and in vitro validation studies of the key enzyme WbPrx6 using the model organism S. digitata.

Lymphatic filariasis (LF), or elephantiasis, is a mosquito-borne parasitic disease that causes severe disability. A neglected tropical disease, LF is the second leading cause of permanent disability worldwide, mainly in tropical and subtropical regions. It is caused by Wuchereria bancrofti (90 %), Brugia malayi, and Brugia timori. The Current treatments are limited, cannot reverse chronic damage, and may cause side effects or resistance. This study aims to identify the key pharmacophore features in potent leads of major antioxidant enzymes (Cu/Zn SOD1, Prx6, Tpx1, GPx and GST) of W. bancrofti, which have already been demonstrated to have significant macrofilaricidal activity. Based on the author's previously reported in silico findings, we performed in vitro validation of WbPrx6 potent three-lead using the S. digitata, which is closely related to human filarial parasites, such as W. bancrofti and B. malayi, making it a suitable model organism for comparative studies. The in vitro results indicated that the lead compound (ChemBridge ID: 42133744) showed a better inhibition profile than ivermectin. Furthermore, we have also identified pharmacophore features of potential leads in the major antioxidant enzymes through ligand-based modelling. The leads were categorized into two groups based on IC50 values: those with lower IC50 values shared AAHR and AARR motifs, while those with higher IC50 values shared AHRR and ADHR motifs. These pharmacophore features, along with their distinct geometrical properties, offer valuable insights for the optimization of future drug candidates targeting W. bancrofti to combat LF.