Binding of GSH conjugates to π-GST: A cross-docking approach

The high degree of flexibility characterizing the members of the GST protein family is supposed to be an evolution-resolved feature related to the detoxifying role of these enzymes. Many evidences suggest that overexpression of these enzymes may be implicated in the development of acquired resistance to antitumor agents. Among the most effective GST inhibitors, GSH conjugates have been found to be particularly promising because of their low toxicity. Here, we used a cross docking approach based on an ensemble of X-ray structures of GST bound complexes to model the effects of protein flexibility on the binding of GSH conjugates. We showed that our multitarget approach, allows to analyze the impact of protein flexibility and induced fit effects in GSH conjugate docking to GST. Moreover, the inclusion of conserved water molecules in the model allowed to include a further source of target variability and improve the performances in the docking of GSH conjugates through an enhanced description of the GSH moiety interactions. Therefore, a map of ligand–protein interactions reflecting the target variability included in the docking model was retraced and used to gain a thorough insight about the way GSH conjugates bind to GST.

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► Cross docking of GSH-conjugates at GST based on an ensemble of X-ray structures.
► Analysis of the impact of GST flexibility on ligand docking.
► Inclusion of explicit water molecules in the target model.
► Mapping and scoring of the ligand interactions with GST ensemble.