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J Comput Aided Mol Des. 2016 Mar;30(3):229-36. doi: 10.1007/s10822-016-9898-z. Epub 2016 Feb 10.

A k-nearest neighbor classification of hERG K(+) channel blockers.

Author information

1
Bioorganic and Biophysical Chemistry Laboratory, Department of Chemistry and Biomedical Sciences, Linnaeus University Centre for Biomaterials Chemistry, Linnaeus University, 391 82, Kalmar, Sweden. swapnil.chavan@lnu.se.
2
eADMET GmbH, Lichtenbergstraße 8, 85748, Garching, Munich, Germany.
3
Bioorganic and Biophysical Chemistry Laboratory, Department of Chemistry and Biomedical Sciences, Linnaeus University Centre for Biomaterials Chemistry, Linnaeus University, 391 82, Kalmar, Sweden.
4
Bioorganic and Biophysical Chemistry Laboratory, Department of Chemistry and Biomedical Sciences, Linnaeus University Centre for Biomaterials Chemistry, Linnaeus University, 391 82, Kalmar, Sweden. ian.nicholls@lnu.se.
5
Department of Chemistry-BMC, Uppsala University, Box 576, 751 23, Uppsala, Sweden. ian.nicholls@lnu.se.

Abstract

A series of 172 molecular structures that block the hERG K(+) channel were used to develop a classification model where, initially, eight types of PaDEL fingerprints were used for k-nearest neighbor model development. A consensus model constructed using Extended-CDK, PubChem and Substructure count fingerprint-based models was found to be a robust predictor of hERG activity. This consensus model demonstrated sensitivity and specificity values of 0.78 and 0.61 for the internal dataset compounds and 0.63 and 0.54 for the external (PubChem) dataset compounds, respectively. This model has identified the highest number of true positives (i.e. 140) from the PubChem dataset so far, as compared to other published models, and can potentially serve as a basis for the prediction of hERG active compounds. Validating this model against FDA-withdrawn substances indicated that it may even be useful for differentiating between mechanisms underlying QT prolongation.

KEYWORDS:

Classification model; Ikr; KCNH2; Toxicity; hERG blockers; k-nearest neighbor (k-NN)

PMID:
26860111
PMCID:
PMC4802000
DOI:
10.1007/s10822-016-9898-z
[Indexed for MEDLINE]
Free PMC Article

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