Challenges in docking 2′-hydroxy and 2′,4′-dihydroxychalcones into the binding site of ALR2

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Polyhydroxylated chalcones are able to efficiently inhibit aldose reductase (ALR2; EC 1.1.1.21), an enzyme implicated in the development of diabetic complications. In this study, we performed docking experiments on a series of 38 2′-hydroxy and 2′,4′-dihydroxychalcones with measured inhibitory activities. We demonstrate that docking the chalcones into a single ALR2 active site conformation oversimplifies the attempt to find a probable binding model. Scoring functions exerted relative low agreement concerning a common ALR2 conformation, and suggest that relative to the substituents, chalcones bind to different ALR2 conformations. We found plausible binding modes of 2′,4′-dihydroxychalones for both closed- and open-state conformations of the ALR2 active site, while 5′-chloro, 2′-hydroxychalcones would bind into an ITB (2-(carboxymethyl)-1,3,3-trioxo-benzo[e][1,2]benzothiazole-4-carboxylic acid)-like binding site conformation. The relative poor reliability of docking programs to recognize a ligand binding into a closed- or open-form conformation of the ALR2 binding site was highlighted by a cross-docking experiment of the native ligands. In this context, we employed conditional interference forests to build classification models aiming to predict the conformational state of the ALR2 ligand-binding site in complex with chalcone derivatives. Internally and externally validated models suggest that 2′-hydroxy and 2′,4′-dihydroxichalones leave the specificity pocket closed. Another issue discussed in the current paper concerns the errors related to the average position of the atoms in the crystals, which can heavily influence the docking poses. The diffraction-component precision index (DPI) is able to reflect these errors, but some structures have no calculated values. In a comparative experiment on 55 ALR2 crystal structures, we found the Blow DPI to better approximate the Cruickshank DPI compared to Goto.