Molecular dynamics/quantum mechanics guided designing of natural products based prodrugs of Epalrestat

Abstract

Over activated molecular target ALR2 of polyol pathway and oxidative stress are two well established pathological indicators in diabetic complications. In present study, mutual prodrugs of Epalrestat and natural product based antioxidants were designed, synthesized and evaluated. In silico techniques such as molecular dynamic simulations and quantum mechanical approaches, considering human esterase enzyme (hCE1) as the site of hydrolytic cleavage were employed in designing of these mutual prodrugs. Geometrical parameters (distance and Burgi-Dunitz angle favorable for nucleophilic attack) and quantum mechanical parameters (HOMO-LUMO energy gap), which govern the hydrolytic cleavage of ester prodrugs by esterase enzyme were calculated. Further, on the basis of in silico analysis, mutual prodrugs were synthesized and considering the values of in silico parameters, EPL-GUA (3g) was evaluated for its in vivo antioxidant activity. Results suggested that 3g possess significant antioxidant activity intermediary to control and Epalrestat. Thus, this study has concluded that these mutual prodrugs could be optimized to develop molecules for the management of diabetic complications. � 2018