Springer, Clayton and Sokolnicki, Katherine (2013) “A molecular matched pair analysis of hERG inhibition data”. Chemistry Central Journal, 7 (167). p. 167. ISSN 1752-153X

Abstract

Drugs that bind to the human Ether-a-go-go Related Gene (hERG) potassium channel and block its ion conduction lead to Torsade de Pointes (TdP), a fatal ventricular arrhythmia. Thus, compounds are screened for hERG inhibition in the drug development process, and those found to be active usually cannot be developed and alternatives without hERG inhibition must be found. Knowing which structural transformations reduce hERG binding would be helpful in the lead optimization phase of drug discovery. To identify such transformations, we analyzed compound pairs in the Novartis database with hERG data. This analysis was a comprehensive comparison of all the compounds for which hERG assay data was available. Most molecular transformations have only a single example in the data set; however, a few dozen transformations have enough examples (5 or more) for statistical analysis. For the more highly populated transformations (with 5 to 29 pairs), we observed 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. We also observed that some changes in aromatic ring substituents (for example hydrogen to methoxy) can also reduce hERG binding.

Item Type:	Article
Keywords:	Fingerprint Pairs; hERG; Molecular Pair; Hydroxyl; Molecular Matched Pairs; Cliff Pairs; Extended Connectivity fingerprints (ECFP)
Date Deposited:	12 Oct 2016 00:45
Last Modified:	12 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/9302