Development, interpretation and temporal evaluation of a global QSAR of hERG electrophysiology screening data.
A 'global' model of hERG K(+) channel was built to satisfy three basic criteria for QSAR models in drug discovery: (1) assessment of the applicability domain, (2) assuring that model decisions can be interpreted by medicinal chemists and (3) assessment of model performance after the model was built. A combination of D-optimal onion design and hierarchical partial least squares modelling was applied to construct a global model of hERG blockade in order to maximize the applicability domain of the model and to enhance its interpretability. Additionally, easily interpretable hERG specific fragment-based descriptors were developed. Model performance was monitored, throughout a time period of 15 months, after model implementation. It was found that after this time duration a greater proportion of molecules were outside the model's applicability domain and that these compounds had a markedly higher average prediction error than those from molecules within the model's applicability domain. The model's predictive performance deteriorated within 4 months after building, illustrating the necessity of regular updating of global models within a drug discovery environment.
Gavaghan
Claire L
CL
Computational Toxicology, Safety Assessment, AstraZeneca R&D, Molndal, Sweden. claire.gavaghan@astrazeneca.com
Arnby
Catrin Hasselgren
CH
Blomberg
Niklas
N
Strandlund
Gert
G
Boyer
Scott
S
D004353:Drug Evaluation, Preclinical; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels