Computational identification and experimental validation of anti-filarial lead molecules targeting metal binding/substrate channel residues of Cu/Zn SOD1 from Wuchereria bancrofti

Abstract

Lymphatic filariasis (LF) is a neglected mosquito-borne parasitic disease, widely caused by Wuchereria bancrofti (Wb) in tropical and sub-tropical countries. During a blood meal, the filarial nematodes are transmitted to humans by the infected mosquito. To counter attack the invaded nematodes, the human immune system produces reactive oxygen species. However, the anti-oxidant enzymes of nematodes counteract the host oxidative cytotoxicity. Cu/Zn Superoxide dismutase (SOD1), a member of antioxidant enzymes and are widely used by the nematodes to sustain the host oxidative stress across its lifecycle, hence targeting SOD1 to develop suitable drug molecules would help to overcome the problems related to efficacy and activity of drugs upon different stages of nematodes. In order to find the potent inhibitors, a three-dimensional structure of Cu/Zn WbSOD1 was modelled and the structural stability was analysed through simulation studies. The structure-guided virtual screening approach has been used to identify lead molecules from the ChemBridge based on the docking score, ADMET properties and protein–ligand complex stability analysis. The identified compounds were observed to interact with the copper, metal binding residues (His48, His63, His80 and His120) and catalytically important residue Arg146, which play a crucial role in the disproportionation of incoming superoxide radicals of Cu/Zn WbSOD1. Further, in vitro validation of the selected leads in the filarial worm Setaria digitata exhibited higher inhibition and better IC₅₀ compared to the standard drug ivermectin. Thus, the identified leads could potentially inhibit enzyme activity, which could subsequently act as drug candidates to control LF.

Communicated by Ramaswamy H. Sarma

Keywords:

• Elephantiasis
• W. bancrofti
• anti-filarial
• SOD1
• molecular dynamics simulations
• virtual screening

Acknowledgements

The authors are grateful to the management of SASTRA Deemed University for providing all necessary facilities. KS thankfully acknowledges DST-SERB for providing financial support in the form of research projects (No: EMR/2017/002841 and No: CVD/2020/000604) to conduct the study. MS sincerely acknowledges DST-SERB for financial assistance. Authors thank the Supercomputing Facility for Bioinformatics and Computational Biology (SCFBio), IIT Delhi for computational resources. Authors like to thank Dr. Venkatasubramanian U, Associate Professor and Mr. Adithyan J, Research Scholar, School of Chemical and Biotechnology, SASTRA Deemed University for their help and suggestion in vitro experiments. Authors also thank Dr. R. Velusamy, M.V.Sc., Ph.D., Assistant Professor and Head, Department of Veterinary Parasitology, Veterinary College and Research Institute Orathanadu, Thanjavur, Tamil Nadu, India for authenticating the filarial worm S. digitata.

Disclosure statement

The authors declare they have no competing interests.

Authors’ contributions

Muthusamy Sureshan: Data Curation, Investigation, Visualization, Validation, Writing - Original Draft. Dhamodharan Prabhu: Data Curation, Investigation, Visualization, Writing – Review & Editing. Kadhirvel Saraboji: Conceptualization, Writing - Review & Editing, Resources, Supervision, Funding acquisition.

Additional information

Funding

The research work was fully supported by DST-SERB CRG, Government of India (No: EMR/2017/002841) granted to Dr. K. Saraboji, SASTRA Deemed University.