Predictive toxicology modeling: Protocols for exploring hERG classification and Tetrahymena pyriformis end point predictions
Resource
J. Chem. Inf. Model., 52, 1660-1673
Journal
Journal of Chemical Information and Modeling
Journal Volume
52
Journal Issue
6
Pages
1660-1673
Date Issued
2012
Author(s)
Abstract
The inclusion and accessibility of different methodologies to explore chemical data sets has been beneficial to the field of predictive modeling, specifically in the chemical sciences in the field of Quantitative Structure-Activity Relationship (QSAR) modeling. This study discusses using contemporary protocols and QSAR modeling methods to properly model two biomolecular systems that have historically not performed well using traditional and three-dimensional QSAR methodologies. Herein, we explore, analyze, and discuss the creation of a classification human Ether-a-go-go Related Gene (hERG) potassium channel model and a continuous Tetrahymena pyriformis (T. pyriformis) model using Support Vector Machine (SVM) and Support Vector Regression (SVR), respectively. The models are constructed with three types of molecular descriptors that capture the gross physicochemical features of the compounds: (i) 2D, 2 1/2D, and 3D physical features, (ii) VolSurf-like molecular interaction fields, and (iii) 4D-Fingerprints. The best hERG SVM model achieved 89% accuracy and the three-best SVM models were able to screen a Pubchem data set with an accuracy of 97%. The best T. pyriformis model had an R2 value of 0.924 for the training set and was able to predict the continuous end points for two test sets with R2 values of 0.832 and 0.620, respectively. The studies presented within demonstrate the predictive ability (classification and continuous end points) of QSAR models constructed from curated data sets, biologically relevant molecular descriptors, and Support Vector Machines and Support Vector Regression. The ability of these protocols and methodologies to accommodate large data sets (several thousands compounds) that are chemically diverse - and in the case of classification modeling unbalanced (one experimental outcome dominates the data set) - allows scientists to further explore a remarkable amount of biological and chemical information. © 2012 American Chemical Society.
Other Subjects
Classification (of information); Computational chemistry; Molecular graphics; Point contacts; Support vector machines; Support vector regression; Vectors; Classification models; End point predictions; Human ether-a-go-go related gene (hERG); Molecular interaction fields; Physicochemical features; Quantitative structure-activity relationship modeling; Support vector regression (SVR); Tetrahymena pyriformis; Predictive analytics; ERG1 potassium channel; potassium channel HERG; animal; article; chemical structure; classification; drug effect; quantitative structure activity relation; support vector machine; Tetrahymena pyriformis; toxicology; Animals; Ether-A-Go-Go Potassium Channels; Models, Molecular; Quantitative Structure-Activity Relationship; Support Vector Machines; Tetrahymena pyriformis; Toxicology
Type
journal article
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