<i>In Silico</i> Screening of Sesquiterpene Lactones as Aldose Reductase Inhibitors

Abstract

Aldose reductase, a key enzyme of the polyol pathway catalyses NADPH-dependent reduction of glucose to sorbitol. Increased activity of this enzyme is considered a major factor contributing to the development of diabetic complications hence could be an important target in the treatment of these complications. In this work, a database of sesquiterpenes was prepared and screened for their drug-like properties based on the Lipinski’s rule of 5. The co-crystallised structure of aldose reductase was obtained from the Protein Data
bank and prepared for docking. In silico docking experiments was performed on Autodock tools using 198 sesquiterpene lactones that passed screening, and compounds with the lowest binding energy and favourable binding interactions were selected for molecular docking simulation. Six of the best ranking compounds selected had binding energies ranging from–11.96 Kcal/mol to -9.45 Kcal/mol  and were comparable to the energy of the standard inhibitor Idd594 used in the study. They also show good complementarity in their binding to the residues of the binding pocket. The results suggest that dehydrooopodin (1), 11(S),13-dihydrolactucopicrin (2), and Chrysanin (3) offered potential inhibitory activities toward aldose reductase and may serve as lead compounds for in vivo validation as aldose reductase inhibitors.

Keywords: Sesquiterpene lactones, Aldose reductase, Binding energy, Molecular docking, Autodock