Monte Carlo method for predicting of cardiac toxicity: hERG blocker compounds

Toxicol Lett. 2016 May 27:250-251:42-6. doi: 10.1016/j.toxlet.2016.04.010. Epub 2016 Apr 8.

Abstract

The estimation of the cardiotoxicity of compounds is an important task for the drug discovery as well as for the risk assessment in ecological aspect. The experimental estimation of the above endpoint is complex and expensive. Hence, the theoretical computational methods are very attractive alternative of the direct experiment. A model for cardiac toxicity of 400 hERG blocker compounds (pIC50) is built up using the Monte Carlo method. Three different splits into the visible training set (in fact, the training set plus the calibration set) and invisible validation sets examined. The predictive potential is very good for all examined splits. The statistical characteristics for the external validation set are (i) the coefficient of determination r(2)=(0.90-0.93); and (ii) root-mean squared error s=(0.30-0.40).

Keywords: CORAL software; Cardiac toxicity; Monte Carlo method; OECD principles; QSAR.

MeSH terms

  • Cardiotoxicity
  • Computer Simulation*
  • Dose-Response Relationship, Drug
  • ERG1 Potassium Channel / antagonists & inhibitors*
  • ERG1 Potassium Channel / metabolism
  • Heart Diseases / chemically induced*
  • Heart Diseases / metabolism
  • Humans
  • Models, Biological*
  • Models, Statistical
  • Molecular Structure
  • Monte Carlo Method*
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / toxicity*
  • Quantitative Structure-Activity Relationship
  • Reproducibility of Results
  • Risk Assessment
  • Software

Substances

  • ERG1 Potassium Channel
  • KCNH2 protein, human
  • Potassium Channel Blockers