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Inhibition of C298S mutant of human aldose reductase for antidiabetic applications: Evidence from in silico elementary mode analysis of biological network model
Author(s) -
Khan Saif,
Bhardwaj Tulika,
Somvanshi Pallavi,
Mandal Raju K.,
Dar Sajad A.,
Jawed Arshad,
Wahid Mohd,
Akhter Naseem,
Lohani Mohtashim,
Alouffi S.,
Haque Shafiul
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26904
Subject(s) - aldose reductase , polyol pathway , sorbitol , rosmarinic acid , sorbitol dehydrogenase , in silico , chemistry , mutant , diabetes mellitus , biochemistry , aldehyde reductase , pharmacology , enzyme , biology , endocrinology , gene , antioxidant
Human aldose reductase (hAR) is the key enzyme in sorbitol pathway of glucose utilization and is implicated in the etiology of secondary complications of diabetes, such as, cardiovascular complications, neuropathy, nephropathy, retinopathy, and cataract genesis. It reduces glucose to sorbitol in the presence of NADPH and the major cause of diabetes complications could be the change in the osmotic pressure due to the accumulation of sorbitol. An activated form of hAR (activated hAR or ahAR) poses a potential obstacle in the development of diabetes drugs as hAR‐inhibitors are ineffective against ahAR. The therapeutic efficacy of such drugs is compromised when a large fraction of the enzyme (hAR) undergoes conversion to the activated ahAR form as has been observed in the diabetic tissues. In the present study, attempts have been made to employ systems biology strategies to identify the elementary nodes of human polyol metabolic pathway, responsible for normal metabolic states, followed by the identification of natural potent inhibitors of the activated form of hAR represented by the mutant C298S for possible antidiabetic applications. Quantum Mechanical Molecular Mechanical docking strategy was used to determine the probable inhibitors of ahAR. Rosmarinic acid was found as the most potent natural ahAR inhibitor and warrants for experimental validation in the near future.