Tuning out of hERG.
A number of drug withdrawals in recent years have been related to cardiovascular toxicity associated with undesirable blockade of the hERG potassium channel. A promiscuous target, hERG has been demonstrated to interact with pharmaceuticals of widely varying structure. Computational and statistical modeling efforts encompassing homology modeling, pharmacophore and quantitative structure-activity relationship models, and also various classification methods, are aimed at defining the molecular features that confer hERG inhibitory activity and understanding the structure-activity relationships that govern hERG-drug interactions. The organization-wide adoption of hERG models is driven by their ability to produce specific and testable structural hypotheses that lead to compounds devoid of hERG liability.
Aronov
Alex M
AM
Vertex Pharmaceuticals Inc, 130 Waverly St, Cambridge, MA 02139-4242, USA. alex_aronov@vrtx.com
D000818:Animals; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000737:chemistry / Q000145:classification; D021281:Quantitative Structure-Activity Relationship
D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers