Comprehensive Approach to in silico Identification and in vitro Validation of Anti-Filarial Lead Molecules Targeting the Dimer Interface of Thioredoxin Peroxidase 1 in Wuchereria bancrofti: A Progress in Anti-Filariasis Drug Development

Abstract Lymphatic filariasis (LF) remains a significant health challenge for populations in developing countries, including India. LF is a parasitic disease transmitted by mosquitoes, caused by three types of nematodes: Wuchereria bancrofti, Brugia malayi , and Brugia timori , prevalent in tropical and subtropical regions. Filarial nematodes are transmitted to humans by infected mosquitoes carrying L3 larvae during a blood meal. The human immune system generates reactive oxygen species (ROS) in response to the invading nematodes. Nevertheless, the nematode's antioxidant enzymes effectively counteract the oxidative cytotoxicity induced by the host. The enzyme thioredoxin peroxidase 1 (TPx1) is a member of the peroxiredoxin family, which facilitates the conversion of hydrogen peroxide (H 2 O 2 ) into water (H 2 O), which is highly used by nematodes to maintain oxidative stress in the host throughout their life cycle. Therefore, developing appropriate therapeutic compounds by targeting TPx1 might aid in resolving difficulties with treatment efficacy and activity at various stages of filarial parasitic worms. To find the potent inhibitors, we modelled the three-dimensional structure of Wb TPx1, and its dynamic stability was assessed by molecular dynamic (MD) simulation studies. A structure-based virtual screening approach was used to find the most promising leads from the small molecule collection, focusing on the dimer interface region of Wb TPx1. The predicted in silico ADMET profiles for the top-ranked hits revealed that the non-toxic lead compounds had the greatest docking score, ranging from − 7.410 kcal/mol to -6.887 kcal/mol, and the identified leads showed higher affinity to Wb TPx1 than Hs TPx1 based on the cross-docking studies. Throughout the simulation of the Wb TPx1-lead complex, the lead molecules exhibited stability and remained intact within the binding site. Furthermore, the in vitro validation of the chosen leads based on computational results in the filarial worm Setaria digitata exhibited higher inhibition and better IC 50 than the standard drug ivermectin. Hence, the identified leads have the potential to inhibit enzyme activity, serving as possible drug candidates for the control of LF.