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.