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Discovery of potent inhibitors targeting Glutathione S-transferase of Wuchereria bancrofti: a step toward the development of effective anti-filariasis drugs

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Abstract

Lymphatic filariasis (LF) is one of the major health problems for the human kind in developing countries including India. LF is caused by three major nematodes namely Wuchereria bancrofti, Brugia malayi, and Brugia timori. The recent statistics of World Health Organization (WHO) showed that 51 million people were affected and 863 million people from 47 countries around worldwide remain threatened by LF. Among them, 90% of the filarial infection was caused by the nematode W. bancrofti. Approved drugs were available for the treatment of LF but many of them developed drug resistance and no longer effective in all stages of the infection. In the current research work, we explored the Glutathione S-transferase (GST) of W. bancrofti, the key enzyme responsible for detoxification that catalyzes the conjugation of reduced GSH (glutathione) to xenobiotic compounds. Initially, we analyzed the stability of the WbGST through 200 ns MD simulation and further structure-based virtual screening approach was applied by targeting the substrate binding site to identify the potential leads from small molecule collection. The in silico ADMET profiles for the top-ranked hits were predicted and the predicted non-toxic lead molecules showed the highest docking score in the range of − 12.72 kcal/mol to − 11.97 kcal/mol. The cross docking of the identified hits with human GST revealed the potential binding specificity of the hits toward WbGST. Through WbGST–lead complex simulation, the lead molecules were observed to be stable and also intactly bound within the binding site of WbGST. Based on the computational results, the five predicted non-toxic molecules were selected for the in vitro assay. The molecules showed significant percentage of inhibition against the filarial worm Setaria digitata which is the commonly used model organism to evaluate the filarial activity. In addition, the molecules also showed better IC50 than the standard drug ivermectin. The identified lead molecules will lay a significant insight for the development of new drugs with higher specificity and lesser toxicity to control and treat filarial infections.

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Acknowledgements

The Authors are grateful to the management of SASTRA Deemed University for providing all necessary facilities. The authors thankfully acknowledge the high-performance computational facility in the School of Computing at SASTRA Deemed University for providing computational resources to complete the simulation studies. The authors like to thank Dr. U Venkatasubramanian, Associate Professor, and Mr. J Adithyan, Research Scholar, School of Chemical and Biotechnology, SASTRA Deemed University, for their help and suggestion in vitro experiments. The Authors also thank to 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.

Funding

KS thankfully acknowledges DST-SERB CRG for providing financial support in the form of research projects (No: EMR/2017/002841 and No: CVD/2020/000604) and the Central University of Punjab for the Research Seed Money (CUPB/Acad./2022/1194, Dated 19.05.2022) to conduct the study.

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Authors and Affiliations

  1. Department of Bioinformatics, Biomolecular Crystallography Lab, School of Chemical & Biotechnology, SASTRA Deemed University, Thanjavur, 613401, India

    Muthusamy Sureshan

  2. Research and Development Wing, Sree Balaji Medical College and Hospital, Bharath Institute of Higher Education and Research, Chennai, 600 044, India

    Dhamodharan Prabhu

  3. Department of Biochemistry, Centre for Drug Discovery, Karpagam Academy of Higher Education, Coimbatore, 641021, India

    Sundarraj Rajamanikandan

  4. Department of Computational Sciences, Central University of Punjab, Bathinda, 151401, Punjab, India

    Kadhirvel Saraboji

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  1. Muthusamy Sureshan
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MS, DP, and SR contributed to data curation, investigation, visualization, validation, and writing–original draft. KS contributed to conceptualization, writing–review and editing, resources, supervision, and funding acquisition. The final version of the manuscript submitted was approved by all authors.

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Sureshan, M., Prabhu, D., Rajamanikandan, S. et al. Discovery of potent inhibitors targeting Glutathione S-transferase of Wuchereria bancrofti: a step toward the development of effective anti-filariasis drugs. Mol Divers 28, 765–785 (2024). https://doi.org/10.1007/s11030-023-10617-7

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