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Structure-based design, synthesis and biological evaluation of β-glucuronidase inhibitors

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Abstract

Using structure-based virtual screening approach, a coumarin derivative (1) was identified as β-glucuronidase inhibitor. A focused library of coumarin derivatives was synthesized by eco-benign version of chemical reaction, and all synthetic compounds were characterized by using spectroscopy. These compounds were found to be inhibitor of β-glucuronidase with IC50 values in a micromolar range. All synthetic compounds exhibited interesting inhibitory activity against β-glucuronidase, however, their potency varied substantially from IC50 = 9.9–352.6 µM. Of twenty-one compounds, four exhibited a better inhibitory profile than the initial hit 1. Interestingly, compounds 1e, 1k, 1n and 1p exhibited more potency than the standard inhibitor with IC50 values 34.2, 21.4, 11.7, and 9.9 µM, respectively. We further studied their dose responses and also checked our results by using detergent Triton ×-100. We found that our results are true and not affected by detergent.

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Acknowledgments

The authors are thankful to Higher Education Commission (HEC) Pakistan for providing financial support under “National Research Program for Universities” to Project No. 20-1394.

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Authors and Affiliations

  1. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Khalid M. Khan, Nida Ambreen, Shagufta Naureen, Saima Rasheed & Mohammad Iqbal Choudhary

  2. Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300, Bandar Puncak Alam, Selangor D. E., Malaysia

    Muhammad Taha

  3. Faculty of Applied Science, UiTM, 40450, Shah Alam, Selangor, Malaysia

    Muhammad Taha

  4. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Sobia A. Halim &  Zaheer-ul-Haq

  5. PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi, 75280, Pakistan

    Shahnaz Perveen

  6. Department of Chemistry, Karakoram International University, Gilgit-Baltistan, Gilgit, 15100, Pakistan

    Sajjad Ali

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  1. Khalid M. Khan
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Correspondence to Khalid M. Khan.

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Khan, K.M., Ambreen, N., Taha, M. et al. Structure-based design, synthesis and biological evaluation of β-glucuronidase inhibitors. J Comput Aided Mol Des 28, 577–585 (2014). https://doi.org/10.1007/s10822-014-9745-z

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