Identification of Putative Plant-Based ALR-2 Inhibitors to Treat Diabetic Peripheral Neuropathy

Abstract

Diabetic peripheral neuropathy (DPN) is a common diabetes complication (DM). Aldose reductase -2 (ALR-2) is an oxidoreductase enzyme that is most extensively studied therapeutic target for diabetes-related complications that can be inhibited by epalrestat, which has severe adverse effects; hence the discovery of potent natural inhibitors is desired. In response, a pharmacophore model based on the properties of eplarestat was generated. The specified pharmacophore model searched the NuBBE_DB database of natural compounds for prospective lead candidates. To assess the drug-likeness and ADMET profile of the compounds, a series of in silico filtering procedures were applied. The compounds were then put through molecular docking and interaction analysis. In comparison to the reference drug, four compounds showed increased binding affinity and demonstrated critical residue interactions with greater stability and specificity. As a result, we have identified four potent inhibitors: ZINC000002895847, ZINC000002566593, ZINC000012447255, and ZINC000065074786, that could be used as pharmacological niches to develop novel ALR-2 inhibitors.

Keywords: ADMET; NuBBEDB; molecular docking; pharmacophore; structure-based drug design.

Figure 1

Generated pharmacophore model exploiting eplarestat.

Figure 2

A plot of polar surface area (PSA) versus ALogP in ADMET analysis of filtered substances, with % and % confidence limit ellipses corresponding to the blood–brain barrier (BBB) and intestinal absorption, respectively.

Figure 3

Superimposed bioactive structure of epalrestat bound in the binding pocket of ALR-2 (PDB ID: 4JIR) (green stick model) and the docked epalrestat (grey stick model) with an RMSD of 0.89 Å.

Figure 4

The top four filtered compounds aligned to the generated pharmacophore, where the green sphere indicates hydrogen bond acceptor, the blue sphere indicates hydrophobic, and the yellow sphere indicates sulfur interactions.

Figure 5

Molecular docking view of the compounds at the binding sites of ALR-2 (PDB ID: 4JIR). The stereo image of the docked complex containing the compound and receptor protein is presented on the left side, whereas the 2D view of the interactions between compounds and 4JIR is presented on the right side. Discovery Studio was used to construct the diagrams; hydrogen bonds are depicted in the green dashed line, hydrophobic interactions in the pink dashed line, and sulfur interactions in the yellow dashed line. The distance between them is displayed in angstroms. The amino acid residues in a protein structure were each given a three-letter code, and the compound is displayed in a ball-and-stick format. (A) epalrestat 3D view, (B) epalrestat 2D view, (C) ZINC000002895847 3D view, (D) ZINC000002895847 2D view, (E) ZINC000002566593 3D view, (F) ZINC000002566593 2D view, (G) ZINC000012447255 3D view, (H) ZINC000012447255 2D view, (I) ZINC000065074786 3D view, (J) ZINC000065074786 2D view.