title: Discovery of Influenza A virus neuraminidase inhibitors using support vector machine and Naïve Bayesian models.
abstract: Neuraminidase (NA) is a critical enzyme in the life cycle of influenza virus, which is known as a successful paradigm in the design of anti-influenza agents. However, to date there are no classification models for the virtual screening of NA inhibitors. In this work, we built support vector machine and Naïve Bayesian models of NA inhibitors and non-inhibitors, with different ratios of active-to-inactive compounds in the training set and different molecular descriptors. Four models with sensitivity or Matthews correlation coefficients greater than 0.9 were chosen to predict the NA inhibitory activities of 15,600 compounds in our in-house database. We combined the results of four optimal models and selected 60 representative compounds to assess their NA inhibitory profiles in vitro. Nine NA inhibitors were identified, five of which were oseltamivir derivatives with large C-5 substituents exhibiting potent inhibition against H1N1 NA with IC50 values in the range of 12.9-185.0 nM, and against H3N2 NA with IC50 values between 18.9 and 366.1 nM. The other four active compounds belonged to novel scaffolds, with IC50 values ranging 39.5-63.8 μM against H1N1 NA and 44.5-114.1 μM against H3N2 NA. This is the first time that classification models of NA inhibitors and non-inhibitors are built and their prediction results validated experimentally using in vitro assays.
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Lian
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Fang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.
authors.forename: Xiaocong
authors.initials: X
authors.lastname: Pang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China. liuailin@imm.ac.cn.|Beijing Key Laboratory of Drug Target Research and Drug Screening, Beijing, 100050, People's Republic of China. liuailin@imm.ac.cn.|State Key Laboratory of Bioactive Substance and Function of Natural Medicines, 1 Xian Nong Tan Street, Beijing, 100050, People's Republic of China. liuailin@imm.ac.cn.
authors.forename: Ai-Lin
authors.initials: AL
authors.lastname: Liu
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China.|Beijing Key Laboratory of Drug Target Research and Drug Screening, Beijing, 100050, People's Republic of China.|State Key Laboratory of Bioactive Substance and Function of Natural Medicines, 1 Xian Nong Tan Street, Beijing, 100050, People's Republic of China.
authors.forename: Guan-Hua
authors.initials: GH
authors.lastname: Du
mesh_terms: D001499:Bayes Theorem; D019295:Computational Biology / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology*; D053122:Influenza A Virus, H3N2 Subtype / Q000201:enzymology*; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D060388:Support Vector Machine
chemical_list: D004791:Enzyme Inhibitors; D009439:Neuraminidase
keywords: H1N1; H3N2; Influenza virus; Naïve Bayesian; Neuraminidase inhibitor; SVM; Support vector machine; Virtual screening