Dataset Information

ToxiM: A Toxicity Prediction Tool for Small Molecules Developed Using Machine Learning and Chemoinformatics Approaches.

ABSTRACT: The experimental methods for the prediction of molecular toxicity are tedious and time-consuming tasks. Thus, the computational approaches could be used to develop alternative methods for toxicity prediction. We have developed a tool for the prediction of molecular toxicity along with the aqueous solubility and permeability of any molecule/metabolite. Using a comprehensive and curated set of toxin molecules as a training set, the different chemical and structural based features such as descriptors and fingerprints were exploited for feature selection, optimization and development of machine learning based classification and regression models. The compositional differences in the distribution of atoms were apparent between toxins and non-toxins, and hence, the molecular features were used for the classification and regression. On 10-fold cross-validation, the descriptor-based, fingerprint-based and hybrid-based classification models showed similar accuracy (93%) and Matthews's correlation coefficient (0.84). The performances of all the three models were comparable (Matthews's correlation coefficient = 0.84-0.87) on the blind dataset. In addition, the regression-based models using descriptors as input features were also compared and evaluated on the blind dataset. Random forest based regression model for the prediction of solubility performed better (R2 = 0.84) than the multi-linear regression (MLR) and partial least square regression (PLSR) models, whereas, the partial least squares based regression model for the prediction of permeability (caco-2) performed better (R2 = 0.68) in comparison to the random forest and MLR based regression models. The performance of final classification and regression models was evaluated using the two validation datasets including the known toxins and commonly used constituents of health products, which attests to its accuracy. The ToxiM web server would be a highly useful and reliable tool for the prediction of toxicity, solubility, and permeability of small molecules.

SUBMITTER: Sharma AK

PROVIDER: S-EPMC5714866 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

ToxiM: A Toxicity Prediction Tool for Small Molecules Developed Using Machine Learning and Chemoinformatics Approaches.

Sharma Ashok K AK Srivastava Gopal N GN Roy Ankita A Sharma Vineet K VK

Frontiers in pharmacology 20171130

The experimental methods for the prediction of molecular toxicity are tedious and time-consuming tasks. Thus, the computational approaches could be used to develop alternative methods for toxicity prediction. We have developed a tool for the prediction of molecular toxicity along with the aqueous solubility and permeability of any molecule/metabolite. Using a comprehensive and curated set of toxin molecules as a training set, the different chemical and structural based features such as descripto ...[more]

PMID: 29249969

Similar Datasets

Project description:Different types of chemicals and products may exhibit various health risks when administered into the human body. For toxicity reasons, the number of new drugs entering the market through the conventional drug development process has been reduced over the years. However, with the advent of big data and artificial intelligence, machine learning techniques have emerged as a potential solution for predicting toxicity and ensuring efficient drug development and chemical safety. An ML model for toxicity prediction can reduce experimental costs and time while addressing ethical concerns by drastically reducing the need for animals and clinical trials. Herein, MolToxPred, an ML-based tool, has been developed using a stacked model approach to predict the potential toxicity of small molecules and metabolites. The stacked model consists of random forest, multi-layer perceptron, and LightGBM as base classifiers and Logistic Regression as the meta classifier. For training and validation purposes, a comprehensive set of toxic and non-toxic molecules is curated. Different structural and physicochemical-based features in the form of molecular descriptors and fingerprints were employed. MolToxPred utilizes a comprehensive feature selection process and optimizes its hyperparameters through Bayesian optimization with stratified 5-fold cross-validation. In the evaluation phase, MolToxPred achieved an AUROC of 87.76% on the test set and 88.84% on an external validation set. The McNemar test was used as the post-hoc test to determine if the stacked models' performance was significantly different compared to the base learners. The developed stacked model outperformed its base classifiers and an existing tool in the literature, reaffirming its better performance. The hypothesis is that the incorporation of a diverse set of data, the subsequent feature selection, and a stacked ensemble approach give MolToxPred the edge over other methods. In addition to this, an attempt has been made to identify structural alerts responsible for endpoints of the Tox21 data to determine the association of a molecule with a plausible downstream pathway of action. MolToxPred may be helpful for drug discovery and regulatory pipelines in pharmaceutical and other industries for in silico toxicity prediction of small molecule candidates.

Project description:The drug-resistant strains of Mycobacterium tuberculosis (M.tb) are evolving at an alarming rate, and this indicates the urgent need for the development of novel antitubercular drugs. However, genetic mutations, complex cell wall system of M.tb, and influx-efflux transporter systems are the major permeability barriers that significantly affect the M.tb drugs activity. Thus, most of the small molecules are ineffective to arrest the M.tb cell growth, even though they are effective at the cellular level. To address the permeability issue, different machine learning models that effectively distinguish permeable and impermeable compounds were developed. The enzyme-based (IC50) and cell-based (minimal inhibitory concentration) data were considered for the classification of M.tb permeable and impermeable compounds. It was assumed that the compounds that have high activity in both enzyme-based and cell-based assays possess the required M.tb cell wall permeability. The XGBoost model was outperformed when compared to the other models generated from different algorithms such as random forest, support vector machine, and naïve Bayes. The XGBoost model was further validated using the validation data set (21 permeable and 19 impermeable compounds). The obtained machine learning models suggested that various descriptors such as molecular weight, atom type, electrotopological state, hydrogen bond donor/acceptor counts, and extended topochemical atoms of molecules are the major determining factors for both M.tb cell permeability and inhibitory activity. Furthermore, potential antimycobacterial drugs were identified using computational drug repurposing. All the approved drugs from DrugBank were collected and screened using the developed permeability model. The screened compounds were given as input in the PASS server for the identification of possible antimycobacterial compounds. The drugs that were retained after two filters were docked to the active site of 10 different potential antimycobacterial drug targets. The results obtained from this study may improve the understanding of M.tb permeability and activity that may aid in the development of novel antimycobacterial drugs.

Dataset Information

ToxiM: A Toxicity Prediction Tool for Small Molecules Developed Using Machine Learning and Chemoinformatics Approaches.

Publications

ToxiM: A Toxicity Prediction Tool for Small Molecules Developed Using Machine Learning and Chemoinformatics Approaches.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets