Computational prediction of hERG blockers using homology modelling, molecular docking and QuaSAR studies

Abstract

A full-length three-dimensional structure of the tetrameric potassium ion channel (hERG Kv11.1) including the N- and C-terminal domains was built, with a diameter of 6 Å and 12 Å between the K + selectivity filter and the pore cavity residue Tyr652 of opposite subunits. Further docking studies with a set of 233 structurally known blockers have shown that compounds bind near the inner vestibule of the pore channel, as well as the helix-IV region of the voltage sensor domain (VSD) in the alpha subunit. The residues of hERG, Gly626, Phe627, Gly628, Tyr652 and Phe656 of the pore channel and Arg488 of VSD plays an important role in ligand binding and hERG blockage. The conducted QuaSAR model is statistically significant, with R2 of 0.72 in predicting the hERG blocking activity. Furthermore, QuaSAR descriptors employing computer-assisted multiple regression procedure reveal that increase in hydrophobicity with higher number of aromatic rings are favorable for the binding affinity of hERG blockers. Additionally, the pIC50 values of 25 commercial compounds screened using structure-based pharmacophore model also show binding to the selectivity filter and pore cavity of hERG potassium channel like the known hERG blockers with a wide range of inhibition from weak to strong blockage predicting to have proarrhythmic potential.