A fingerprint pair analysis of hERG inhibition data

BACKGROUND: Drugs that bind to the human Ether-a-go-go Related Gene (hERG) potassium channel and block its ion conduction can lead to Torsade de Pointes (TdP), a fatal ventricular arrhythmia. Thus, compounds are screened for hERG inhibition in the drug development process; those found to be active face a difficult road to approval. Knowing which structural transformations reduce hERG binding would be helpful in the lead optimization phase of drug discovery. RESULTS: To identify such transformations, we carried out a comprehensive analysis of all approximately 33,000 compound pairs in the Novartis internal database which have IC(50) values in the dofetilide displacement assay. Most molecular transformations have only a single example in the data set; however, a few dozen transformations have sufficient numbers for statistical analysis. CONCLUSIONS: We observe that transformations which increased polarity (for example adding an oxygen, or an sp(2) nitrogen), decreased lipophilicity (removing carbons), or decreased positive charge consistently reduced hERG inhibition between 3- and 10-fold. The largest observed reduction in hERG was from a transformation from imidazole to methyl tetrazole. We also observe that some changes in aromatic ring substituents (for example hydrogen to methoxy) can also reduce hERG binding in vitro.