A fingerprint pair analysis of hERG inhibition data

Chemistry Central Journal

Clayton Springer¹  Katherine L Sokolnicki¹ 

[1] Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA

关键词: Extended connectivity fingerprints (ECFP);    Cliff pairs;    Molecular matched pairs;    Hydroxyl;    Molecular pair;    hERG;    Fingerprint pairs;   

Others  :  787827
DOI  :  10.1186/1752-153X-7-167

 received in 2013-06-20, accepted in 2013-09-10,  发布年份 2013

【 摘 要 】

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 IC₅₀ 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 sp² 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.

【 授权许可】

   
2013 Springer and Sokolnicki; licensee Chemistry Central Ltd.

【 图 表 】

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