A virtual screening method for prediction of the HERG potassium channel liability of compound libraries.
A computer-based method has been developed for prediction of the hERG (human ether-à-go-go related gene) K(+)-channel affinity of low molecular weight compounds. hERG channel blockage is a major concern in drug design, as such blocking agents can cause sudden cardiac death. Various techniques were applied to finding appropriate molecular descriptors for modeling structure-activity relationships: substructure analysis, self-organizing maps (SOM), principal component analysis (PCA), partial least squares fitting (PLS), and supervised neural networks. The most accurate prediction system was based on an artificial neural network. In a validation study, 93 % of the nonblocking agents and 71 % of the hERG channel blockers were correctly classified. This virtual screening method can be used for general compound-library shaping and combinatorial library design.
Roche
Olivier
O
F. Hoffmann-La Roche AG, Pharmaceuticals Division, 4070 Basel, Switzerland.
Trube
Gerhard
G
Zuegge
Jochen
J
Pflimlin
Pascal
P
Alanine
Alexander
A
Schneider
Gisbert
G
D027682:Cation Transport Proteins; D020650:Combinatorial Chemistry Techniques; D004268:DNA-Binding Proteins; D016208:Databases, Factual; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D016014:Linear Models; D015394:Molecular Structure; D016571:Neural Networks, Computer; D017711:Nonlinear Dynamics; D015221:Potassium Channels / Q000737:chemistry*; D024642:Potassium Channels, Voltage-Gated; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG