QM/MM analysis, synthesis and biological evaluation of epalrestat based mutual-prodrugs for diabetic neuropathy and nephropathy

Abstract

Herein, a quantum mechanics/molecular mechanics (QM/MM) based biotransformation study was performed on synthetically feasible mutual-prodrugs of epalrestat which have been identified from an in-house database developed by us. These prodrugs were submitted to quantum polarized ligand docking (QPLD) with the CES1 enzyme followed by MM-GBSA calculation. Electronic aspects of transition state of these prodrugs were also considered to study the catalytic process through density functional theory (DFT). ADMET analysis of prodrugs was then carried out to assess the drug-likeness. On the basis of in-silico results, the best five prodrugs were synthesized and further evaluated for their neuroprotective and nephroprotective potential in high-fat diet-streptozotocin (HFD-STZ) induced diabetes in rat model. Clinically relevant molecular manifestations of diabetic complications (DC) including aldose reductase (ALR2) activity and oxidative stress markers such as reduced glutathione (GSH), catalase (CAT), and thiobarbituric acid reactive substances (TBARS) were determined in blood plasma as well as tissues of the brain and kidneys. The histopathological examination of these organs was also carried out to see the improvement in structural deformities caused due to neuropathy and nephropathy. Finally, in-vivo pharmacokinetic study was performed for the best two prodrugs to assess the improvement in biopharmaceutical attributes of parent drugs. Overall, EP-G-MFA and EP-MFA have significantly reduced the hyperglycemia-induced ALR2 activity, levels of oxidative stress markers, and manifested about a two-fold increase in the biological half-life (T_1/2) of parent drugs. The overall findings of this study suggest that methyl ferulate conjugated prodrugs of epalrestat may be considered as potential protective agents in diabetic neuropathy and nephropathy.

Keywords: ALR2; Epalrestat; Mutual-prodrug; Nephropathy; Neuropathy; Pharmacokinetics; QM/MM.