title: Docking and molecular dynamics studies toward the binding of new natural phenolic marine inhibitors and aldose reductase.
abstract: Phenolic marine natural product is a kind of new potential aldose reductase inhibitors (ARIs). In order to investigate the binding mode and inhibition mechanism, molecular docking and dynamics studies were performed to explore the interactions of six phenolic inhibitors with human aldose reductase (hALR2). Considering physiological environment, all the neutral and other two ionized states of each phenolic inhibitor were adopted in the simulation. The calculations indicate that all the inhibitors are able to form stable hydrogen bonds with the hALR2 active pocket which is mainly constructed by residues TYR48, HIS110 and TRP111, and they impose the inhibition effect by occupying the active space. In all inhibitors, only La and its two ionized derivatives La_ion1 and La_ion2, in which neither of the ortho-hydrogens of 3-hydroxyl is substituted by Br, bind with hALR2 active residues using the terminal 3-hydroxyl. While, all the other inhibitors, at least one of whose ortho-sites of 3- and 6-hydroxyls are substituted by Br substituent which take much electron-withdrawing effect and steric hindrance, bind with hALR2 through the lactone group. This means that the Br substituent can effectively regulate the binding modes of phenolic inhibitors. Although the lactone bound inhibitors have relatively high RMSD values, our dynamics study shows that both binding modes are of high stability. For each inhibitor molecule, the ionization does not change its original binding mode, but it does gradually increase the binding free energy, which reveals that besides hydrogen bonds, the electrostatic effect is also important to the inhibitor-hALR2 interaction.
authors.affiliation: Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai 810001, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Wang
authors.forename: Baoping
authors.initials: B
authors.lastname: Ling
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Yourui
authors.initials: Y
authors.lastname: Suo
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhangyu
authors.initials: Z
authors.lastname: Yu
authors.forename: Chengbu
authors.initials: C
authors.lastname: Liu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D048289:Imidazolidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017433:Protein Structure, Secondary; D012236:Rhodanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D053778:Thiazolidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D048289:Imidazolidines; D009281:Naphthalenes; D053778:Thiazolidines; C040550:tolrestat; C038131:epalrestat; D012236:Rhodanine; C077139:fidarestat; D000449:Aldehyde Reductase; C026411:sorbinil