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Studies on filarial GST as a target for antifilarial drug development—in silico and in vitro inhibition of filarial GST by substituted 1,4-naphthoquinones

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Abstract

Eleven 1,4-naphthoquinone analogues with different amino substitutions at position 3 of the quinone ring earlier reported for macrofilaricidal activity were selected and screened against purified cytosolic GST isolated from the bovine filarial worm Setaria digitata and IC50 values were determined. Of the 11 compounds tested, 8 showed good inhibition against S. digitata GST. The IC50 values of the most effective macrofilaricidal compounds—11 [2-(4-methylpiperazin-1-yl)naphthalene-1,4-dione] and 9 {2-[(1,3-dimethylbutyl)amino]naphthalene -1,4-dione}—were 0.872 and 0.994 mM, respectively. Compounds 9 and 11 were further studied for type of enzyme inhibition and found to exhibit competitive and uncompetitive inhibition kinetics, respectively, with respect to substrate GSH. All 11 compounds were in agreement with Lipinski’s rule of five and passed through the FAFDrugs ADME/tox filter. Molecular docking was carried out using the modeled 3D structure of wbGST PDB ID:1SFM as receptor and substituted naphthoquinones as ligands using AutoDock 4.0. The binding energy of nine compounds varied from −9.15 to −6.58 Kcal mol−1, whereas compounds 8 and 10 did not show any binding to the receptor. Among the compounds studied, compound 7 {2-[3-(diethylamino) propyl]aminonaphthalene-1,4-dione} showed maximum affinity towards wbGST as it exhibited the lowest binding energy, followed by compounds 11 and 9. However compound 7 was not macrofilaricidal while 11 and 9 exhibited macrofilaricidal activity. The results of in silico and in vitro studies with the synthesized 1,4 -naphthoquinone analogues on filarial GST and in vitro macrofilaricidal activity against adult bovine filarial worm S. digitata open up a promising biochemical target for antifilarial drug development.

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Acknowledgments

N.M. expresses sincere gratitude to the Department of Science and Technology (DST), Government of India for funding [Grant SR/SO/HS-83/2005] to conduct this study. The authors are grateful to Dr. P. Jambulingam, Director, Vector Control Research Center, Pondicherry, for his encouragement during the study. The technical assistance of Mrs. Anila Kumari and Mr. Srinivasan is also acknowledged.

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Authors and Affiliations

  1. Vector Control Research Center, Indian Council of Medical Research, Indira Nagar, Pondicherry, 605006, India

    Nisha Mathew, Lakshmy Srinivasan, Twinkle Karunan, Elango Ayyanar & Kalyanasundaram Muthuswamy

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  1. Nisha Mathew
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  2. Lakshmy Srinivasan
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  3. Twinkle Karunan
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  4. Elango Ayyanar
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  5. Kalyanasundaram Muthuswamy
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Correspondence to Nisha Mathew.

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ESM 1

Docking binding energy (mean lowest) values and the number of members of each cluster (DOC 117 kb)

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Mathew, N., Srinivasan, L., Karunan, T. et al. Studies on filarial GST as a target for antifilarial drug development—in silico and in vitro inhibition of filarial GST by substituted 1,4-naphthoquinones. J Mol Model 17, 2651–2657 (2011). https://doi.org/10.1007/s00894-010-0952-9

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  • DOI: https://doi.org/10.1007/s00894-010-0952-9

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