Structure-based designing of anti-filarial molecules targeting the key antioxidant enzyme glutathione peroxidase (GPx) of Wuchereria bancrofti: An integrated in silico and in vitro approach.

Lymphatic filariasis (LF) or Wuchereriasis, also known as elephantiasis, is a debilitating and disfiguring parasitic disease transmitted by mosquitoes and is categorized as a neglected tropical disease (NTD). Globally, 90 % of filarial infections are caused by W. bancrofti. Moreover, the present drugs have adverse side effects, inadequate specificity, exhibit drug resistance and are ineffective in treating all stages of infection. This study aimed to identify therapeutic lead molecules by targeting the key enzyme glutathione peroxidase (GPx) in the W. bancrofti life cycle, which is essential for nematode survival against host-induced oxidative stress. The WbGPx structure was modelled, the molecular dynamics (MD) simulation assessed the structural stability and computational structure-guided screening was employed to identify potent hit molecules. ADMET profiling revealed non-toxic hits with binding affinities (-7.628 to -7.152 kcal/mol) and showed higher specificity for WbGPx over HsGPx. Furthermore, MD simulations confirmed the stable and compact binding of hit molecules over 100 ns, based on structural analysis and stability profiles. Additionally, the differences and changes in the binding of the hit molecules with WbGPx were studied and visualized using essential dynamics, porcupine plots, and free energy landscape (FEL) analyses to elucidate the impact of ligand binding on the enzyme's conformational dynamics and to identify energetically favorable states. Further, in vitro validation using Setaria digitata, showed that the potent leads of WbGPx exhibited significant inhibition and better IC50 profiles than the standard drug molecule ivermectin. These molecules provide a strong foundation for the development of novel therapeutic agents for improved management and treatment of LF.