Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities

Figure 1. The hERG blockers with the best activity/molecular weight (ligand efficiency, LE) and activity/lipophilicity (Lipophilic efficiency, LipE) ratios.

Figure 2. A plot between first two principal components (PC) illustrating descriptor space of 166 training set (hollow circles) and 41 test set (filled circles).

Figure 3. Plot representing the correlation between q2 and r2 values of the final GRIND model at different latent variables (LV-1-5).

Figure 4. Experimental and predicted hERG inhibitory potential (pIC50) values of OSM database (test set II).

Figure 5. The plot of observed vs. predicted pIC50 values of the test set I (filled square), test set II (filled diamonds) projected on observed vs. predicted pIC50 values of the training set (hollow square).

Figure 6. PLS co-efficient correlogram plot representing the GRIND variables exhibiting direct (positive values) and inverse(negative values) correlation with hERG inhibitory potency(pIC50) values.

Figure 7. Shows the most relevant regions identified by GRIND model for ligand-hERG interaction. The contours define the virtual receptor site (VRS). DRY-DRY (yellow contours) representing the mutual distance of 14.0–14.4 A° between two hydrophobic molecular interaction fields (DRY1 and DRY2), TIP-TIP (green contours) feature showing a distance of 20.0–20.4 A° between two steric hotspots (TIP1 and TIP2), DRY-TIP representing a distance of 18.4–18.8 A° between hydrophobic molecular interaction field (DRY1: yellow) and steric hotspot (TIP2: green). DRY-N1 representing hydrophobic molecular interaction field (DRY1: yellow) at a distance of 10.8–11.8 A° from amide nitrogen representing hydrogen bond donor feature (N1: blue contours) that contribute positively to hERG blockage potential (pIC50). Interestingly, the molecular features mapped by DRY-DRY correlogram complement the molecular features translated by the highest peak of DRY-TIP cross-correlogram peaks shown in Figure 6. Both DRY-DRY and DRY-TIP auto and cross-correlograms corresponds to the hydrophobic moieties attached at both sides of the linker region.

Figure 8. Shows 3D structural features of least active hERG inhibitors depicted by N1-N1 (blue contours) O-N1 (red and blue contours) PLS coefficient correlograms.

Figure 9. Showing statistically significant hERG inhibition pharmacophore model obtained using Droperidol docked in the closed conformational state of hERG as template. The pharmacophore consists of two aromatic, one hydrophobic and one hydrogen bond acceptor feature.

Figure 10. (A) 2D structure of selected compound from ChemBridge database. (B) Step ramp protocol. (C) Plot of current (pA) traces vs. time(s): Green sweep is showing maximum current passing through the channel when no drug is applied to the channel. The gradual decrease in current peak is showing channel inhibition in response to various dose concentrations. (D) Dose-response curve showing percentage blockade of hERG current against various drug concentration.

Figure 11. (A) 2D structure of selected compound from OSM database. (B) Step ramp protocol. (C) Plot of current (pA) traces vs. time (s): Green sweep is showing maximum current passing through the channel when no drug is applied to the channel. The gradual decrease in current peak is showing channel inhibition in response to various dose concentrations. (D) Dose-response curve showing percentage blockade of hERG current against various drug concentration.