Biomedical Engineering Reference
In-Depth Information
Prediction of hERG Channel Inhibition Using
In Silico Techniques
Andrea Schiesaro and Gerhard F. Ecker
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
2 Long QT Syndrome ......................................................................... 193
3 Structure of the hERG Channel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
4 Ligand-Based Approaches .................................................................. 195
4.1 Pharmacophore Models .............................................................. 195
4.2 3D-QSAR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
4.3 2D-QSAR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
4.4 1D-QSAR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
4.5 Classification Models ................................................................. 207
4.6 Matched Molecular Pairs . . ........................................................... 216
5 Structure-Based Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
5.1 Homology Models of the hERG Channel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
5.2 hERG Inhibition and Drug Trapping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
5.3 Amino Acids Involved in hERG Inhibition . . . . . ................................... 220
5.4 Hydrogen Bonds with Ser624, Thr623 or Val625? . ............................... 222
5.5 Role of Gly648 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
5.6 Which Subunits Are Involved in Drug Binding? . . . . . . . ........................... 223
5.7 Influence of Para-Substituents on the Phenyl Ring . . .............................. 224
5.8 Two or Three Binding Interactions? ................................................ 225
5.9 Docking Studies and Prediction of hERG Binding Affinity . . . . . . ................. 225
5.10 Case Studies: Docking Studies and Improvement of the Selectivity . . . . . . . . . . . . . . 227
5.11 Orthogonal Binding Site? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
5.12 Docking Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Abstract Drug-induced long QT syndrome still represents a major risk for late-
stage clinical failure of drug candidates. One of the main factors inducing long
QT is inhibition of cardiac hERG channels. Early prediction of potential hERG
