Modeling hERG Channel Liability: From Structural Insight to Highly Accurate Qualitative and Quantitative Models

Figures

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  1. Chemical structures of hERG blockers with varying activities and different therapeutic indications. The three ligands observed in cryo-EM hERG structures–astemizole, E-4031, and pimozide −together with terfenadine and fexofenadine, all share a piperidine core.

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  2. (a) Superposition of the apo hERG channel (PDB ID: 8ZYN, light blue) and hERG structures in complex with astemizole (PDB ID: 8ZYO, green), E-4031 (PDB ID: 8ZYP, yellow), and pimozide (PDB ID: 8ZYN, teal). (b) Electrostatic surfaces of the ligand-binding pockets of apo-hERG (PDB ID: 8ZYN), illustrating the C4 symmetry.

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  3. Seven core residues form the box-shaped ligand-binding pocket of the hERG channel. (a) Side view and (b) top view of the bottom of the binding pocket formed by residues S621, T623, S624, and V625, colored in light blue. (c) Side view and (d) top view of the pocket walls formed by residues S649, Y652, and F656, colored in green. The pocket coordinates are taken from the apo hERG channel (PDB ID: 8ZYN), whereas the ligand astemizole, shown in stick representation, is taken from PDB ID 8ZYO.

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  4. (a) Superposition of the three hERG blockers in the binding mode: astemizole (green), E-4031 (yellow) and pimozide (teal). (b) Astemizole interacting with the hERG ligand binding pocket, with key hydrogen bonds indicated by yellow dashed lines. (c) Ligand binding sites of apo, astemizole-bound, E-4031-bound, and pimozide-bound hERG channels, shown with semitransparent surfaces. The side chains of the key residue Y652 were displayed as lines, and the ligands as sticks. For comparison, astemizole was positioned in the ligand binding site of the apo hERG structure. (d) Superposition of ligand binding pockets of apo (light blue) and astemizole-bound (green) hERG channels, with the side chains of F656 shown in a space-filling representation.

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  5. (a) Area under the ROC curve (ROC-AUC) and accuracy for five classification models using different split ratios (90/10, 80/20, 70/30, 60/40, and 50/50). Error bars represent the standard deviation from ten repeated experiments for each split scheme. (b) Distribution of pIC50 values for the misclassified compounds in the test sets.

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  6. (a) Experimental pIC50 of 7,619 molecules in the test sets of ten SVR models plotted against predicted values with the regression line (red), and deviation lines (±0.5 log units in green). (b) Distribution of pIC50 values of the 7,772 compounds used in regression.

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  7. Experimental pIC50 values of the 1,133 molecules in the validation set plotted against the predicted values, with the regression line shown in red, for (a) the original data set and (b) the corrected data set.