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Subject: search.filters.subject.W. bancrofti

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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
    (Institute for Ionics, 2023-02-16T00:00:00) Sureshan, Muthusamy; Prabhu, Dhamodharan; Rajamanikandan, Sundarraj; Saraboji, Kadhirvel
    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. Graphical abstract: [Figure not available: see fulltext.] � 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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    Computational identification and experimental validation of anti-filarial lead molecules targeting metal binding/substrate channel residues of Cu/Zn SOD1 from Wuchereria bancrofti
    (Taylor and Francis Ltd., 2022-10-28T00:00:00) Sureshan, Muthusamy; Prabhu, Dhamodharan; Kadhirvel, Saraboji
    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. � 2022 Informa UK Limited, trading as Taylor & Francis Group.
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    Designing specific inhibitors against dihydrofolate reductase of W. bancrofti towards drug discovery for lymphatic filariasis
    (Springer, 2022-03-15T00:00:00) Sureshan, Muthusamy; Rajamanikandan, Sundarraj; Srimari, Srikanth; Prabhu, Dhamodharan; Jeyakanthan, Jeyaraman; Saraboji, Kadhirvel
    Lymphatic filariasis (LF) is one among the leading neglected diseases caused by mosquitoe-borne parasite Wuchereria bancrofti to humans. Though drugs are available for the treatment of LF, all of which are not effective in all stages and moreover majority of these drugs have been reported with resistance. There is a need for effective new drugs which affect the parasite irrespective of its lifecycle and counter the drug resistance mechanisms. In the present study, we have explored the key enzyme dihydrofolate reductase (DHFR) as the potential target for developing drugs against LF. We have modelled dihydrofolate reductase structure and analysed its stability through the 200�ns simulation studies. Computer-assisted screening method found five non-toxic potent hit molecules with a docking score of ? 13.86 to ? 13.54�kcal/mol. Interestingly, we observed that the identified hit molecules are more specific to W. bancrofti DHFR than human DHFR due to electrostatic charge variations in the binding cavity. Higher specificity could increase the therapeutic efficacy and also minimize cross-reactivity with human targets. We have also found that the identified hit molecules have better glide score and energy than the reported DHFR inhibitors of W. bancrofti. Better score and energy values depict that the identified hit molecules could inhibit the DHFR activity efficiently. The DFT analysis predicted the regions in the hit molecules with higher probability of chemical reactivity and also potential sites to enhance the binding efficiency. Our findings provide new scaffolds for the development of DHFR inhibitors, which can be efficiently formulated to treat LF. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.