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Experimental validation and docking studies of flavone derivatives on aldose reductase involved in diabetic retinopathy, neuropathy, and nephropathy

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Abstract

The enzyme aldoreductase which plays an important role in pathogenesis of diabetic retinopathy, neuropathy, and nephropathy was purified from bovine lens, and its inhibitory activity was studied with the synthesized flavone derivatives 1-(2-hydroxyphenyl)ethanone as the starting material. Experimental study revealed that 2-chloroflavone shows less inhibitory activity of 60–70% than other flavones used in the study. To validate experimental results computationally, docking studies of new flavone derivatives synthesized were performed with the enzyme aldose reductase, and the results indicate that 3-iodo, 4-methyl, 5-chloroflavone and 2-chloroflavone bind with higher and lesser affinities. Docking studies with site directed mutagenesis of Val47Ile, Tyr48His, Pro121Phe, Trp219Tyr, Cys298Ala, Leu300Pro, Ser302Arg, and Cys303Asp of the enzyme altered the inhibition activity of aldose reductase. The regression value (R 2) of 0.81 between the docking scores of the known inhibitors and the experimental logIC50 indicates the reliability of the docking studies. Biological activity and carcinogenic properties predict that 3-iodo, 4-methyl, 5-chloroflavone is the best flavone inhibitor against aldose reductase.

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Acknowledgments

The authors are thankful to the Director, Global institute of Biotechnology, Himayatnagar, Hyderabad for his kind support for providing the software necessary to carry out this study.

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Authors and Affiliations

  1. Department of Genetics, Osmania University, Hyderabad, 500 007, India

    Pagadala Nataraj Sekhar, P. B. Kavi Kishor & Lakkireddy Anandareddy

  2. School of Chemical Sciences, S. R. T. M. University, Nanded, 431 606, India

    P. K. Zubaidha & A. M. Hashmi

  3. School of Life Sciences, S. R. T. M. University, Nanded, 431 606, India

    T. A. Kadam & G. Gyananath

  4. Laboratory of Biomolecular Modelling, Division Biochemistry, Molecular and Structural Biology, Department of Chemistry, Katholieke University, Leuven, Belgium

    Marc De Maeyer

  5. Srivenkateswara University, Tirupathi, 517 501, India

    K. Praveen Kumar, B. Vijaya Bhaskar & T. Munichandrababu

  6. Srinidhi Institute of Science and Technology, Hyderabad, 500 007, India

    G. Jayasree

  7. CARISM, SASTRA University, Thanjavur, India

    P. V. B. S. Narayana

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  1. Pagadala Nataraj Sekhar
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  2. P. B. Kavi Kishor
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  7. Marc De Maeyer
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  12. P. V. B. S. Narayana
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  13. G. Gyananath
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Correspondence to Pagadala Nataraj Sekhar.

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Nataraj Sekhar, P., Kavi Kishor, P.B., Zubaidha, P.K. et al. Experimental validation and docking studies of flavone derivatives on aldose reductase involved in diabetic retinopathy, neuropathy, and nephropathy. Med Chem Res 20, 930–945 (2011). https://doi.org/10.1007/s00044-010-9412-4

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  • DOI: https://doi.org/10.1007/s00044-010-9412-4

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