Predicting repurposed drugs targeting the NS3 protease of dengue virus using machine learning-based QSAR, molecular docking, and molecular dynamics simulations.
Y Chongjun, A M S Nasr, M A M Latif, M B A Rahman, E Marlisah, B A Tejo
{"title":"Predicting repurposed drugs targeting the NS3 protease of dengue virus using machine learning-based QSAR, molecular docking, and molecular dynamics simulations.","authors":"Y Chongjun, A M S Nasr, M A M Latif, M B A Rahman, E Marlisah, B A Tejo","doi":"10.1080/1062936X.2024.2392677","DOIUrl":null,"url":null,"abstract":"<p><p>Dengue fever, prevalent in Southeast Asian countries, currently lacks effective pharmaceutical interventions for virus replication control. This study employs a strategy that combines machine learning (ML)-based quantitative-structure-activity relationship (QSAR), molecular docking, and molecular dynamics simulations to discover potential inhibitors of the NS3 protease of the dengue virus. We used nine molecular fingerprints from PaDEL to extract features from the NS3 protease dataset of dengue virus type 2 in the ChEMBL database. Feature selection was achieved through the low variance threshold, F-Score, and recursive feature elimination (RFE) methods. Our investigation employed three ML models - support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost) - for classifier development. Our SVM model, combined with SVM-RFE, had the best accuracy (0.866) and ROC_AUC (0.964) in the testing set. We identified potent inhibitors on the basis of the optimal classifier probabilities and docking binding affinities. SHAP and LIME analyses highlighted the significant molecular fingerprints (e.g. ExtFP69, ExtFP362, ExtFP576) involved in NS3 protease inhibitory activity. Molecular dynamics simulations indicated that amphotericin B exhibited the highest binding energy of -212 kJ/mol and formed a hydrogen bond with the critical residue Ser196. This approach enhances NS3 protease inhibitor identification and expedites the discovery of dengue therapeutics.</p>","PeriodicalId":21446,"journal":{"name":"SAR and QSAR in Environmental Research","volume":" ","pages":"707-728"},"PeriodicalIF":2.3000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"SAR and QSAR in Environmental Research","FirstCategoryId":"93","ListUrlMain":"https://doi.org/10.1080/1062936X.2024.2392677","RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/30 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Dengue fever, prevalent in Southeast Asian countries, currently lacks effective pharmaceutical interventions for virus replication control. This study employs a strategy that combines machine learning (ML)-based quantitative-structure-activity relationship (QSAR), molecular docking, and molecular dynamics simulations to discover potential inhibitors of the NS3 protease of the dengue virus. We used nine molecular fingerprints from PaDEL to extract features from the NS3 protease dataset of dengue virus type 2 in the ChEMBL database. Feature selection was achieved through the low variance threshold, F-Score, and recursive feature elimination (RFE) methods. Our investigation employed three ML models - support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost) - for classifier development. Our SVM model, combined with SVM-RFE, had the best accuracy (0.866) and ROC_AUC (0.964) in the testing set. We identified potent inhibitors on the basis of the optimal classifier probabilities and docking binding affinities. SHAP and LIME analyses highlighted the significant molecular fingerprints (e.g. ExtFP69, ExtFP362, ExtFP576) involved in NS3 protease inhibitory activity. Molecular dynamics simulations indicated that amphotericin B exhibited the highest binding energy of -212 kJ/mol and formed a hydrogen bond with the critical residue Ser196. This approach enhances NS3 protease inhibitor identification and expedites the discovery of dengue therapeutics.
期刊介绍:
SAR and QSAR in Environmental Research is an international journal welcoming papers on the fundamental and practical aspects of the structure-activity and structure-property relationships in the fields of environmental science, agrochemistry, toxicology, pharmacology and applied chemistry. A unique aspect of the journal is the focus on emerging techniques for the building of SAR and QSAR models in these widely varying fields. The scope of the journal includes, but is not limited to, the topics of topological and physicochemical descriptors, mathematical, statistical and graphical methods for data analysis, computer methods and programs, original applications and comparative studies. In addition to primary scientific papers, the journal contains reviews of books and software and news of conferences. Special issues on topics of current and widespread interest to the SAR and QSAR community will be published from time to time.