Docking and Molecular Dynamics Study on the Inhibitory Activity of Coumarins on Aldose Reductase

Abstract

In order to explore the inhibitory mechanism of coumarins toward aldose reductase (ALR2), AutoDock and Gromacs software were used for docking and molecular dynamics studies on 14 coumarins (CM) and ALR2 protease. The docking results indicate that residues TYR48, HIS110, and TRP111 construct the active pocket of ALR2 and, besides van der Waals and hydrophobic interaction, CM mainly interact with ALR2 by forming hydrogen bonds to cause inhibitory behavior. Except for CM1, all the other coumarins take the lactone part as acceptor to build up the hydrogen bond network with active-pocket residues. Unlike CM3, which has two comparable binding modes with ALR2, most coumarins only have one dominant orientation in their binding sites. The molecular dynamics calculation, based on the docking results, implies that the orientations of CM in the active pocket show different stabilities. Orientation of CM1 and CM3a take an unstable binding mode with ALR2; their conformations and RMSDs relative to ALR2 change a lot with the dynamic process. While the remaining CM are always hydrogen-bonded with residues TYR48 and HIS110 through the carbonyl O atom of the lactone group during the whole process, they retain the original binding mode and gradually reach dynamic equilibrium.

Esculetin, a Coumarin Derivative, Inhibits Aldose Reductase Activity in vitro and Cataractogenesis in Galactose-Fed Rats

“…The inhibition of aldose reductase has been proposed as a therapeutic approach to ameliorate or prevent long-term diabetic complications, such as sugar cataracts. Coumarins have a ring structure that is similar to that in flavonoids, and an aldose reductase inhibitory activity of coumarins has also been reported ( Wang et al ., 2008 ). Coumarin, a natural substance found in various plants, is an organic compound in the aroma benzopyrone chemical class and is a colorless crystalline substance in a standard state.…”

Characterization of 6‐propylthiouracil and its interaction with human serum albumin on Au surface by surface‐enhanced Raman scattering

“…The Lamarckian genetic algorithm was performed to find the optimum bind site of the drug to protein. [20] A maximum of 10 conformers were considered for the drug during the docking process. According to the principles of the lowest energy connected with matching quality geometrically between ligand and receptor, the conformer was used for further analysis.…”

Docking and molecular dynamics studies toward the binding of new natural phenolic marine inhibitors and aldose reductase

“…The NPT ensemble and Gromacs force field were applied [22]. Each Ligand/ALR2/NADP + complex was placed in the center of a 72 Å Â 72 Å Â 72 Å cubic box and solvated by SPC/E water molecules, Na + counterions were added to keep the system electrically neutral.…”

“…But their binding modes with ALR2 and the inhibition mechanism are still unknown. Having structural similarities with coumarins we studied before [22], these compounds also share a central lactone group, but the phenolic inhibitors have one additional phenol group at each side of the 5-membered lactone ring (Fig. 3), which make them can bind with ALR2 through either the terminal phenolic hydroxyl group or the central lactone group.…”