Modulation of aldose reductase inhibition by halogen bond tuning.

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Fanfrlik J, Kolar M, Kamlar M, Hurny D, Ruiz FX, Cousido-Siah A, Mitschler A, Rezac J, Munusamy E, Lepsik M, Matejicek P, Vesely J, Podjarny A, Hobza P

Modulation of aldose reductase inhibition by halogen bond tuning.

ACS Chem Biol. 2013 Nov 15;8(11):2484-92. doi: 10.1021/cb400526n. Epub 2013 Sep 17.

PubMed ID

23988122 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(2-{[(4-BROMO-2-FLUOROBENZYL)AMINO]CARBONYL}-5-CHLOROPHENOXY)ACETIC ACID	Aldose reductase	IC 50 (nM)	4.00E+02	7	25	Details