Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations

Abstract

Aldose reductase is involved in the polyol pathway, catalyzing the reduction of glucose to sorbitol. However, due to pronounced binding site adaptations, the enzyme can operate on a broad palette of structurally diverse substrates ranging from small aliphatic and aromatic aldehydes up to steroid-type ligands. A comparative analysis of the presently accessible crystal structures of aldose reductase complexes reveals four binding-competent protein conformations. Additional relevant conformers are detected through molecular dynamics simulations. They indicate an equilibrium of several conformers which is shifted towards the binding-competent geometries upon ligand binding. Such a manifold system with several alternative binding site conformers requires some tailored concepts in virtual screening. We followed two strategies, both successfully suggesting new micromolar inhibitors. In a first attempt, we concentrated on one preferred conformer and performed a virtual screening, assuming that the binding pocket of aldose reductase adopts only this conformation. In a second approach, we followed a ligand superpositioning method. Ligands were extracted in their bound conformations from three different crystal structures, all accommodating the ligands with different active site conformations. After merging these ligands into one supermolecule, mutual alignments were computed, taking candidate ligands from a screening database. The latter strategy also retrieved several structurally new inhibitors of micromolar potency.

Screening and evaluation of rat kidney aldose reductase inhibitory activity of some pyridazine derivatives

“…Results clearly showed that introduction of a substituted pyrazole ring on 2H-pyridazin-3-one and 6-chloropyridazine led to a marked decrease in AR inhibitory potency. This finding is in contrast to many effective AR inhibitory compounds possessing ring systems similar to that of pyrazole such as thiazole (Klebe et al, 2004;Maccari et al, 2005), oxadiazole (Klebe et al, 2004), pyrolidine (Pau et al, 2004), hydantoin, and related cyclic imides (Buyukbingol et al, 1994) (Fig. 2).…”

“…1). In situations of increased glucose flux, sorbitol can accumulate in cells of insulin-dependent glucose uptake, leading to increased osmotic pressure in the cells (Klebe et al, 2004). The pathophysiological activity of AR plays a key role in the development of degenerative long-term diabetic complications such as neuropathy, nephropathy, retinopathy, cardiomyopathy, and cataract formation (Suzen and Buyukbingol, 2003).…”

The Isolation and Characterization of β-Glucogallin as a Novel Aldose Reductase Inhibitor from Emblica officinalis

“…The active site of AKR1B1 consists of two major pockets, the so-called “anionic” pocket and the “specificity” pocket [30]. The active site of AKR1B1 can accommodate a multitude of substrates due to the flexibility of the “specificity pocket” residues [31].…”

Crystal Structures of Mouse 17α-Hydroxysteroid Dehydrogenase (Apoenzyme and Enzyme-NADP(H) Binary Complex): Identification of Molecular Determinants Responsible for the Unique 17α-reductive Activity of this Enzyme

“…However, as shown for h3α-HSD3, certain residues of the steroid-binding site can undergo significant conformational changes dictated, in part, by the shape of the steroid itself, changes that are essential for the correct orientation of the steroid and for the position and stereospecificity of the oxydo-reduction reaction. 14 This binding site adaptation, similar to the "ligand induced-fit mechanism" reported for the aldose reductase, 16 is of major importance for the steroid-binding specificity and is very difficult to predict without determining the crystal structure of these enzymes in complex with their substrates.…”