Molecular Docking Evaluation of Some Natural Phenolic Compounds as Aldose Reductase Inhibitors for Diabetic Complications

Ajmer Singh Grewal, Neelam Sharma, Sukhbir Singh and Sandeep Arora


Aldose Reductase, AR Inhibitors, Diabetic Complications, Flavonoids, Molecular Docking, Phenolic compounds, Polyol Pathway.


The enzyme aldose reductase (AR) is a member of aldoketoreductase super-family which catalyzes the formation of sorbitol from glucose through polyol pathway of glucose catabolism. Reduced sorbitol production via polyol pathway due to AR inhibition is a target of choice for controlling major complications of diabetes. Epalrestat is the only commercially available inhibitor of AR till date,thus, there is a great need to search for more economical, nontoxic and safer inhibitors of AR enzyme. Flavonoids, the polyphenol compounds in plants have been reported for inhibitory effects against AR. The objective of this study is to explore the binding modes of natural phenolic compounds with AR to design safer natural drugs as alternatives to synthetic drugs. We conducted a molecular docking study on some natural phenolic compounds with AR enzyme in complex with the synthetic inhibitor. The overlay of the docked pose of the selected natural phenols with the ARreference inhibitor complex showed that the selected natural compounds have the similar binding pattern with the active site residues of the enzyme as that of co-crystallized inhibitor. The results of docking study showed the best binding affinity of AR with that of 2-(4-hydroxy-3-methoxyphenyl) ethanoic acid and butein, having the lowest binding free energy of –9.8 kcal/mol and –9.7 kcal/mol, respectively. This information can be utilized to design potent, economical and non-toxic natural AR inhibitors from natural phenols for the therapeutics of diabetic complications.

DOI 10.15415/jptrm.2017.52009
  • American Diabetes Association(2014) Diagnosis and classification of diabetes mellitus. Diabetes Care, 37, S81–S90.
  • Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., et al. (2010) The protein data bank. Nucleic Acids Research, 2000; 28(1):2 35–242.
  • Brownlee, M. (2001) Biochemistry and molecular cell biology of diabetic complications. Nature, 414, 813–820.
  • Cade, W. T. (2008) Diabetes-related microvascular and macro vascular diseases in the physical therapy setting. Physical Therapy, 88, 1322–1335.
  • Chethan, S., Dharmesh, S. M., & Malleshi, N. G. (2008) Inhibition of aldose reductase from cataracted eye lenses by finger millet (Eleusinecoracana) polyphenols. Bioorganic & Medicinal Chemistry, 16, 10085–10090.
  • Chung, S. S., & Chung, S. K. (2005) Aldose reductase in diabetic microvascular complications. Current Drug Targets, 6, 475-486.
  • Cumbie, B. C., & Hermayer, K. L. (2007) Current concepts in targeted therapies for the pathophysiology of diabetic microvascular complications. Vascular Health and Risk Management, 3, 823–832.
  • Forbes, J. M., & Cooper, M. E. (2013) Mechanisms of diabetic complications. Physiological Reviews, 93, 137-188.
  • Fuente, J. A., & Manzanaro, S. (2003) Aldose reductase inhibitors from natural sources. Natural Product Reports, 20, 243–251.
  • Goodarzi, M. T., Zal, F., & Malakooti, M. (2006) Inhibitory activity of flavonoids on the lens aldose reductase of healthy and diabetic rats. ActaMedicaIranica, 44, 41–45.
  • Grewal, A. S., Sekhon, B. S., & Lather, V. (2014) Recent updates on glucokinase activators for the treatment of type 2 diabetes mellitus. Mini Reviews in Medicinal Chemistry, 14(7), 585–602.
  • Grewal, A. S., Bhardwaj, S., Pandita, D., Lather, V., & Sekhon, B. S. (2016) Updates on aldose reductase inhibitors for management of diabetic complications and non-diabetic diseases. Mini Reviews in Medicinal Chemistry, 16(2), 120–162.
  • Haraguchi, H., Ohmi, I., Sakai, S., Fukuda, A., Toihara, Y., Fujimoto, T., et al. (1996) Effect of Polygonumhydropiper sulfated flavonoids on lens aldose reductase and related enzymes. Journal of Natural Products, 59, 443–445.
  • International Diabetes Federation. (2013) IDF Diabetes Atlas, 6th Ed., Brussels, Belgium: International Diabetes Federation.
  • Jain, S. V., Bhadoriya, K. S. & Bari, S. B. (2012) QSAR and flexible docking studies of some aldose reductase inhibitors obtained from natural origin. Medicinal Chemistry Research, 21:1665–1676.
  • Jung, H. A., Yoon, N. Y., Kang, S. S., Kim, Y. S., & Choi, J. S. (2008) Inhibitory activities of prenylated flavonoids from Sophoraflavescens against aldose reductase and generation of advanced glycation endproducts. Journal of Pharmacy & Pharmacology, 60, 1227–1236.
  • Kato, A., Higuchi, Y., Goto, H., Kizu, H., Okamoto, T., Asano, N., et al. (2006) Inhibitory effects of Zingiberofficinale Roscoe derived components on aldose reductase activity in vitro and in vivo. Journal of Agricultural and Food Chemistry, 54, 6640–6644.
  • Kohei, K. (2010) Pathophysiology of type 2 diabetes and its treatment policy. Japan Medical Association Journal, 53, 41–46.
  • Lee, E. H., Song, D. G., Lee, J. Y., Pan, C. H., Um, B. H., & Jung, S. H. (2008) Inhibitory effect of the compounds isolated from Rhusverniciflua on aldose reductase and advanced glycation endproducts. Biological and Pharmaceutical Bulletin, 31, 1626–1630.
  • Lee, Y. S., Kim, S. H., Jung, S. H., Kim, J. K., Pan, C. H., & Lim, S. S. (2010) Aldose reductase inhibitory compounds from Glycyrrhizauralensis. Biological and Pharmaceutical Bulletin, 33, 917–921.
  • Lee, D. G., Lee, K. H., Park, K. W., Han, C. K., Ryu, B. Y., Cho, E. J., et al. (2015) Isolation and identification of flavonoids with aldose reductase inhibitory activity from Petasites japonicas. Asian Journal of Chemistry, 27(3), 991–994.
  • Logendra, S., Ribnicky, D. M., Yang, H., Poulev, A., Ma, J., Kennelly, E. J., et al. (2006) Bioassay-guided isolation of aldose reductase inhibitors from Artemisia dracunculus. Phytochemistry, 67, 1539–1546.
  • MarvinSketch version 15.9.21. ChemAxon Ltd.,, 2015.
  • Miteva, M. A., Guyon, F., & Tufféry, P. (2010) Frog 2: Efficient 3D conformation ensemble generator for small compounds. Nucleic Acids Research, 38, W622–627.
  • Mohan, V., & Anbalagan, V. (2013) Expanding role of the Madras Diabetes Research Foundation - Indian Diabetes Risk Score in clinical practice. Indian Journal of Endocrinology and Metabolism, 17, 31–36.
  • Morikawa, T., Xie, H., Wang, T., Matsuda, H., & Yoshikawa, M. (2008) Bioactive constituents from Chinese natural medicines. XXXII. aminopeptidase N and aldose reductase inhibitors from Sinocrassulaindica: structures of sinocrassosides B(4), B(5), C(1), and D(1)-D(3). Chemical and Pharmaceutical Bulletin, 56, 1438–1444.
  • Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., et al. (2009) Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. Journal of Computational Chemistry, 16, 2785–2791.
  • Murata, M., Irie, J., & Homma, S. (1994) Aldose reductase inhibitors from green tea. Journal of Food Science and Technology, 27, 401–405.
  • Muthenna, P., Suryanarayana, P., Gunda, S. K., Petrash, J. M., & Reddy, G. B. (2009) Inhibition of aldose reductase by dietary antioxidant curcumin: mechanism of inhibition, specificity and significance. FEBS Letters, 583, 3637–3642.
  • Nakai, N., Fujii, Y., Kobashi, K., & Nomura, K. (1985) Aldose reductase inhibitors: flavonoids, alkaloids, acetophenones, benzophenones, and spirohydantoins of chroman. Archives of Biochemistry and Biophysics 1985; 239:491–496.
  • Oates, P. J. (2008) Aldose reductase, still a compelling target for diabetic neuropathy. Current Drug Targets, 9, 14–36.
  • Okada, Y., Miyauchi, N., Suzuki, K., Kobayashi, T., Tsutsui, C., Mayuzumi, K., et al. (1995) Search for naturally occurring substances to prevent the complications of diabetes. II. Inhibitory effect of coumarin and flavonoid derivatives on bovine lens aldose reductase and rabbit platelet aggregation. Chemical and Pharmaceutical Bulletin, 43, 1385–1387.
  • Olokoba, A. B., Obateru, O. A., & Olokoba, L. B. (2012) Type 2 diabetes mellitus: a review of current trends. Oman Medical Journal, 27, 269–273.
  • Suzen, S., & Buyukbingol, E. (2003) Recent studies of aldose reductase enzyme inhibition for diabetic complications. Current Medicinal Chemistry, 10, 1329–1352.
  • Tomás-Barberán, F. A., López-Gómez, C., Villar, A., & Tomás-Lorente, F. (1986) Inhibition of lens aldose reductase by Labiatae flavonoids. PlantaMedica, 3, 239–240.
  • Trott, O., & Olson, A. J. (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. Journal of Computational Chemistry, 31, 455–461.
  • Wild, S., Roglic, G., Green, A., Sicree, R., & King, H. (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care, 27, 1047–1053.
  • Yabe-Nishimura, C. (1998) Aldose reductase in glucose toxicity: a potential target for the prevention of diabetic complications. Pharmacological Reviews, 50, 21–33.
  • Zhang, C. L., Wang, Y., Liu, Y. F., Liang, D., Hao, Z.Y., Luo, H., et al. (2016) Two new flavonoid glycosides from Iris tectorum. Phytochemistry Letters, 15, 63–65.