Abstract
Objective: Drug-induced liver injury (DILI) is a major cause of drug withdrawal. The chemical properties of the drug, especially drug metabolites, play key roles in DILI. Our goal is to construct a QSAR model to predict drug hepatotoxicity based on drug metabolites.
Materials and Methods: 64 hepatotoxic drug metabolites and 3,339 non-hepatotoxic drug metabolites were gathered from MDL Metabolite Database. Considering the imbalance of the dataset, we randomly split the negative samples and combined each portion with all the positive samples to construct individually balanced datasets for constructing independent classifiers. Then, we adopted an ensemble approach to make prediction based on the results of all individual classifiers and applied the minimum Redundancy Maximum Relevance (mRMR) feature selection method to select the molecular descriptors. Eventually, for the drugs in the external test set, a Bayesian inference method was used to predict the hepatotoxicity of a drug based on its metabolites.
Results: The model showed the average balanced accuracy=78.47%, sensitivity =74.17%, and specificity=82.77%. Five molecular descriptors characterizing molecular polarity, intramolecular bonding strength, and molecular frontier orbital energy were obtained. When predicting the hepatotoxicity of a drug based on all its metabolites, the sensitivity, specificity and balanced accuracy were 60.38%, 70.00% and 65.19%, respectively, indicating that this method is useful for identifying the hepatotoxicity of drugs.
Conclusions: We developed an in silico model to predict hepatotoxicity of drug metabolites. Moreover, Bayesian inference was applied to predict the hepatotoxicity of a drug based on its metabolites which brought out valuable high sensitivity and specificity.
Keywords: DILI, hepatotoxicity, QSAR, drug metabolites, mRMR, SVM.
Combinatorial Chemistry & High Throughput Screening
Title:Predicting Hepatotoxicity of Drug Metabolites Via an Ensemble Approach Based on Support Vector Machine
Volume: 20 Issue: 10
Author(s): Yin Lu, Lili Liu, Dong Lu, Yudong Cai*, Mingyue Zheng*, Xiaomin Luo*, Hualiang Jiang and Kaixian Chen
Affiliation:
- Institute of Systems Biology, Shanghai University, Shanghai 200444,China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203,China
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203,China
Keywords: DILI, hepatotoxicity, QSAR, drug metabolites, mRMR, SVM.
Abstract: Objective: Drug-induced liver injury (DILI) is a major cause of drug withdrawal. The chemical properties of the drug, especially drug metabolites, play key roles in DILI. Our goal is to construct a QSAR model to predict drug hepatotoxicity based on drug metabolites.
Materials and Methods: 64 hepatotoxic drug metabolites and 3,339 non-hepatotoxic drug metabolites were gathered from MDL Metabolite Database. Considering the imbalance of the dataset, we randomly split the negative samples and combined each portion with all the positive samples to construct individually balanced datasets for constructing independent classifiers. Then, we adopted an ensemble approach to make prediction based on the results of all individual classifiers and applied the minimum Redundancy Maximum Relevance (mRMR) feature selection method to select the molecular descriptors. Eventually, for the drugs in the external test set, a Bayesian inference method was used to predict the hepatotoxicity of a drug based on its metabolites.
Results: The model showed the average balanced accuracy=78.47%, sensitivity =74.17%, and specificity=82.77%. Five molecular descriptors characterizing molecular polarity, intramolecular bonding strength, and molecular frontier orbital energy were obtained. When predicting the hepatotoxicity of a drug based on all its metabolites, the sensitivity, specificity and balanced accuracy were 60.38%, 70.00% and 65.19%, respectively, indicating that this method is useful for identifying the hepatotoxicity of drugs.
Conclusions: We developed an in silico model to predict hepatotoxicity of drug metabolites. Moreover, Bayesian inference was applied to predict the hepatotoxicity of a drug based on its metabolites which brought out valuable high sensitivity and specificity.
Export Options
About this article
Cite this article as:
Lu Yin , Liu Lili , Lu Dong , Cai Yudong *, Zheng Mingyue *, Luo Xiaomin*, Jiang Hualiang and Chen Kaixian, Predicting Hepatotoxicity of Drug Metabolites Via an Ensemble Approach Based on Support Vector Machine, Combinatorial Chemistry & High Throughput Screening 2017; 20 (10) . https://dx.doi.org/10.2174/1386207320666171121113255
DOI https://dx.doi.org/10.2174/1386207320666171121113255 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
Call for Papers in Thematic Issues
Artificial Intelligence Methods for Biomedical, Biochemical and Bioinformatics Problems
Recently, a large number of technologies based on artificial intelligence have been developed and applied to solve a diverse range of problems in the areas of biomedical, biochemical and bioinformatics problems. By utilizing powerful computing resources and massive amounts of data, methods based on artificial intelligence can significantly improve the ...read more
Eco-friendly Agents for Biological Control of Pathogenic Diseases
The discovery of an alternative biological approach to disease management includes work on medicinal products derived from natural sources as a starting point for the development of eco-friendly agents for these diseases and the injuries they cause, as well as reducing human contact with hazardous chemicals and their residues. We ...read more
Emerging trends in diseases mechanisms, noble drug targets and therapeutic strategies: focus on immunological and inflammatory disorders
Recently infectious and inflammatory diseases have been a key concern worldwide due to tremendous morbidity and mortality world Wide. Recent, nCOVID-9 pandemic is a good example for the emerging infectious disease outbreak. The world is facing many emerging and re-emerging diseases out breaks at present however, there is huge lack ...read more
Exploring Spectral Graph Theory in Combinatorial Chemistry
Scope of the Thematic Issue: Combinatorial chemistry involves the synthesis and analysis of a large number of diverse compounds simultaneously. Traditional methods rely on brute force experimentation, which can be time-consuming and resource-intensive. Spectral Graph Theory, a branch of mathematics dealing with the properties of graphs in relation to the ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Photochemical Advanced Oxidation Processes for Water and Wastewater Treatment
Recent Patents on Engineering The Potential of 11C-acetate PET for Monitoring the Fatty Acid Synthesis Pathway in Tumors
Current Pharmaceutical Biotechnology Pharmacoinformatic Approaches to Design Natural Product Type Ligands of ABC-Transporters
Current Pharmaceutical Design Microwave Assisted Synthesis, Biological Characterization and Docking Studies of Pyrimidine Derivatives
Current Microwave Chemistry Insights into Novel Coronavirus Disease 2019 (COVID-19): Current Understanding, Research, and Therapeutic Updates
Recent Patents on Biotechnology Development of 5-Fluorouracil Derivatives as Anticancer Agents
Current Medicinal Chemistry Subject Index to Volume 1
Mini-Reviews in Organic Chemistry A Review of Recent Advancements in Anti-tubercular Molecular Hybrids
Current Medicinal Chemistry QSAR Modeling of Carcinogenic Risk Using Discriminant Analysis and Topological Molecular Descriptors
Current Drug Discovery Technologies Antibacterial Activity of Lipophilic Fluoroquinolone Derivatives
Medicinal Chemistry Beneficial Effects of N-acetylcysteine and N-mercaptopropionylglycine on Ischemia Reperfusion Injury in the Heart
Current Medicinal Chemistry Physiological and Pathophysiological Roles of ATP-Sensitive K+ Channels in Vascular Smooth Muscle
Vascular Disease Prevention (Discontinued) Inhibitors and Modulators of β- and γ-Secretase
Current Topics in Medicinal Chemistry Flavonoids: Prospective Drug Candidates
Mini-Reviews in Medicinal Chemistry CDC25A and B Dual-Specificity Phosphatase Inhibitors: Potential Agents for Cancer Therapy
Current Medicinal Chemistry Design, Synthesis, and Cytotoxicity of Novel 2,4,6-Trisubstituted 1,3,5- triazines Bearing Aryl Hydrazone Moiety as Potent Antitumor Agent
Medicinal Chemistry Bio-Inspired Algorithms Applied to Molecular Docking Simulations
Current Medicinal Chemistry Design and Synthesis of NO-releasing Betulinic Acid Derivatives as Potential Anticancer Agents
Anti-Cancer Agents in Medicinal Chemistry Synthesis and Antitumour Activity of the Primin (2-methoxy-6-n-pentyl-1,4-benzoquinone) and Analogues
Medicinal Chemistry Recent Advances in the New Generation Taxane Anticancer Agents
Medicinal Chemistry