Insights into Substrate and Inhibitor Selectivity among Human GLUT Transporters through Comparative Modeling and Molecular Docking

Abstract

The solute carrier 2 family is composed of 14 transporters, which are members of the major facilitator superfamily. Despite their high physiological importance, there are still many open questions concerning their function and specificity, and in some cases, their physiological substrate is still unknown. To understand the determinants of the substrate and inhibitor specificity, we modeled all human glucose transport carriers (GLUTs) and simulated their interaction with known ligands. Comparative modeling was performed with the @TOME-2 pipeline, employing multiple templates and providing an ensemble of models for each GLUT. We analyzed models in both outward-occluded and inward-open conformations, to compare exofacial and endofacial binding sites throughout the family and understand differences in susceptibility of GLUTs to the inhibitor cytochalasin B. Finally, we employed molecular docking and bioinformatics to identify residues likely critical for recognition of myo-inositol by GLUT13 and urate by GLUT9. These results provide insights into the molecular basis for the specificity for these substrates. In addition, we suggested a potential recognition site of glucosamine by GLUT11 to be evaluated in future experiments.

Therapeutic effects and mechanisms of N-(9,10-anthraquinone-2-ylcarbonyl) xanthine oxidase inhibitors on hyperuricemia

“…The carbonyl, amide, and carboxyl groups on anthraquinone formed hydrogen bonds with amino acid residues respectively, with bond lengths of 3.4, 2.2, 2.0, 2.1, 2.6, and 1.9 Å. The docking sites were essentially the same as those reported in the literature (Ferreira et al, 2019), indicating that the compound NAY could work well with GLUT9, which was consistent with the previous pharmacological activities. Figure 14D shows that the binding energy of NAY and OAT1 is -8.48 kcal/mol.…”

“…uk/) (Jumper et al, 2021;Varadi et al, 2022). The active site of XOD was determined using its original ligand febuxostat, and the active sites of Glut9, OAT1, and OAT3 were determined according to the methods described in the literature (Ferreira et al, 2019;Li et al, 2020). The software Autodock 4.0 was used to carry out molecular docking, according to the method reported in the literature (Steinberger et al, 2000), and then plotted using Pymol software (van Pouderoyen et al, 2001).…”

Identification of druggable small molecule antagonists of the Plasmodium falciparum hexose transporter PfHT and assessment of ligand access to the glucose permeation pathway via FLAG-mediated protein engineering

“…Although WU-1 is a non-competitive inhibitor of PfHT in terms of zero-trans influx (Fig 6), it remains possible that WU-1 is a competitive inhibitor for zero-trans efflux as has been shown for cytochalasin B (CB) [33] and for the HIV protease inhibitor indinavir [31]. Similar to all GLUTs that are inhibited by CB, residues Q282, W388, N411, and W412 (GLUT1 nomenclature) are found in PfHT [34]. When the endofacial ligand CB was used to inhibit glucose uptake in both cell lines, like WU-1, we found that CB was significantly less potent (right-shifted) in inhibiting FTPfHT than PfHT (IC 50 = 29.9 ± 1.8 μM vs 10.9 ± 0.9 μM, p< 0.05, Fig 9B).…”

Integrative transcriptome analysis of SARS-CoV-2 human-infected cells combined with deep learning algorithms identifies two potential cellular targets for the treatment of coronavirus disease

“…The PDSM2 gene encodes a component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins [56]. These two proteins have recently attracted attention for their druggable and therapeutic potential [57,58].…”