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.

Halogen Bonding in Supramolecular Chemistry

“…Hobza and co-workers have recently systematically studied the binding of bromo-and iodobenzene-derived inhibitors of aldose reductase. 320 The ligands bind within the active site of the protein and form an XB between the bromine or iodine atom of the ligand and the backbone carbonyl oxygen of the Thr113 arene core, which modulates the strength of ligand binding, as determined through the measured IC 50 values (the concentration of ligand corresponding to half-maximum enzyme inhibition activity). High-resolution crystal structures of the ligands bound within the protein binding pocket demonstrate that all seven ligands bind in the same manner, and that the structural changes upon fluorine substitution are minimal, while computational techniques demonstrate that both fluorine substitution and bromine-to-iodine exchange result in an increase in the XB interaction energy (Figure 79).…”

The Dominant Role of Chalcogen Bonding in the Crystal Packing of 2D/3D Aromatics

“…A modulation of the X-bond in protein-inhibitor complexes was used to reduce the IC 50 values accordingly. [13,14] Reference interaction energies (DE) for the X-bond are obtained using the highly accurate CCSD(T) calculations. Hartree-Fock (HF) and density funtional theory (DFT) usually give too low DE values.…”

The Interplay between Various σ- and π-Hole Interactions of Trigonal Boron and Trigonal Pyramidal Arsenic Triiodides

“…This has already been demonstrated in model systems [6] as well as in protein-ligand complexes [7,8]. In contrast to our previous studies, we have compared two very similar molecules here.…”