title: In silico prediction of chemical acute oral toxicity using multi-classification methods.
abstract: Chemical acute oral toxicity is an important end point in drug design and environmental risk assessment. However, it is difficult to determine by experiments, and in silico methods are hence developed as an alternative. In this study, a comprehensive data set containing 12, 204 diverse compounds with median lethal dose (LD₅₀) was compiled. These chemicals were classified into four categories, namely categories I, II, III and IV, based on the criterion of the U.S. Environmental Protection Agency (EPA). Then several multiclassification models were developed using five machine learning methods, including support vector machine (SVM), C4.5 decision tree (C4.5), random forest (RF), κ-nearest neighbor (kNN), and naïve Bayes (NB) algorithms, along with MACCS and FP4 fingerprints. One-against-one (OAO) and binary tree (BT) strategies were employed for SVM multiclassification. Performances were measured by two external validation sets containing 1678 and 375 chemicals, separately. The overall accuracy of the MACCS-SVM(OAO) model was 83.0% and 89.9% for external validation sets I and II, respectively, which showed reliable predictive accuracy for each class. In addition, some representative substructures responsible for acute oral toxicity were identified using information gain and substructure frequency analysis methods, which might be very helpful for further study to avoid the toxicity.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , 130 Meilong Road, Shanghai 200237, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Feixiong
authors.initials: F
authors.lastname: Cheng
authors.forename: Zengrui
authors.initials: Z
authors.lastname: Wu
authors.forename: Hanping
authors.initials: H
authors.lastname: Bian
authors.forename: Congying
authors.initials: C
authors.lastname: Xu
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Guixia
authors.initials: G
authors.lastname: Liu
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000284:Administration, Oral; D001499:Bayes Theorem; D003198:Computer Simulation; D008962:Models, Theoretical; D060388:Support Vector Machine; D023382:Toxicity Tests, Acute