title: Modulation of aldose reductase inhibition by halogen bond tuning.
abstract: In this paper, we studied a designed series of aldose reductase (AR) inhibitors. The series was derived from a known AR binder, which had previously been shown to form a halogen bond between its bromine atom and the oxygen atom of the Thr-113 side chain of AR. In the series, the strength of the halogen bond was modulated by two factors, namely bromine-iodine substitution and the fluorination of the aromatic ring in several positions. The role of the single halogen bond in AR-ligand binding was elucidated by advanced binding free energy calculations involving the semiempirical quantum chemical Hamiltonian. The results were complemented with ultrahigh-resolution X-ray crystallography and IC50 measurements. All of the AR inhibitors studied were shown by X-ray crystallography to bind in an identical manner. Further, it was demonstrated that it was possible to decrease the IC50 value by about 1 order of magnitude by tuning the strength of the halogen bond by a monoatomic substitution. The calculations revealed that the protein-ligand interaction energy increased upon the substitution of iodine for bromine or upon the addition of electron-withdrawing fluorine atoms to the ring. However, the effect on the binding affinity was found to be more complex due to the change of the solvation/desolvation properties within the ligand series. The study shows that it is possible to modulate the strength of a halogen bond in a protein-ligand complex as was designed based on the previous studies of low-molecular-weight complexes.
authors.affiliation: Institute of Organic Chemistry and Biochemistry and Gilead Science Research Center, Academy of Sciences of the Czech Republic , Flemingovo nam. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Jindřich
authors.initials: J
authors.lastname: Fanfrlík
authors.forename: Michal
authors.initials: M
authors.lastname: Kolář
authors.forename: Martin
authors.initials: M
authors.lastname: Kamlar
authors.forename: David
authors.initials: D
authors.lastname: Hurný
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Ruiz
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cousido-Siah
authors.forename: André
authors.initials: A
authors.lastname: Mitschler
authors.forename: Jan
authors.initials: J
authors.lastname: Rezáč
authors.forename: Elango
authors.initials: E
authors.lastname: Munusamy
authors.forename: Martin
authors.initials: M
authors.lastname: Lepšík
authors.forename: Pavel
authors.initials: P
authors.lastname: Matějíček
authors.forename: Jan
authors.initials: J
authors.lastname: Veselý
authors.forename: Alberto
authors.initials: A
authors.lastname: Podjarny
authors.forename: Pavel
authors.initials: P
authors.lastname: Hobza
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry; D006219:Halogens / Q000737:chemistry*; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular
chemical_list: D004791:Enzyme Inhibitors; D006219:Halogens; D000449:Aldehyde Reductase