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

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. Experiment...

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Bibliographic Details
Published in:	Medicinal chemistry research Vol. 20; no. 7; pp. 930 - 945
Main Authors:	Nataraj Sekhar, Pagadala, Kavi Kishor, P. B., Zubaidha, P. K., Hashmi, A. M., Kadam, T. A., Anandareddy, Lakkireddy, De Maeyer, Marc, Praveen Kumar, K., Vijaya Bhaskar, B., Munichandrababu, T., Jayasree, G., Narayana, P. V. B. S., Gyananath, G.
Format:	Journal Article
Language:	English
Published:	New York Springer-Verlag 01-09-2011
Subjects:	Biochemistry Biomedical and Life Sciences Biomedicine Cell Biology Original Research Pharmacology/Toxicology Aldose reductase Flavones Docking
Online Access:	Get full text
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Summary:	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 logIC 50 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.
ISSN:	1054-2523 1554-8120
DOI:	10.1007/s00044-010-9412-4