title: Predictions of BuChE inhibitors using support vector machine and naive Bayesian classification techniques in drug discovery.
abstract: Butyrylcholinesterase (BuChE, EC 3.1.1.8) is an important pharmacological target for Alzheimer's disease (AD) treatment. However, the currently available BuChE inhibitor screening assays are expensive, labor-intensive, and compound-dependent. It is necessary to develop robust in silico methods to predict the activities of BuChE inhibitors for the lead identification. In this investigation, support vector machine (SVM) models and naive Bayesian models were built to discriminate BuChE inhibitors (BuChEIs) from the noninhibitors. Each molecule was initially represented in 1870 structural descriptors (1235 from ADRIANA.Code, 334 from MOE, and 301 from Discovery studio). Correlation analysis and stepwise variable selection method were applied to figure out activity-related descriptors for prediction models. Additionally, structural fingerprint descriptors were added to improve the predictive ability of models, which were measured by cross-validation, a test set validation with 1001 compounds and an external test set validation with 317 diverse chemicals. The best two models gave Matthews correlation coefficient of 0.9551 and 0.9550 for the test set and 0.9132 and 0.9221 for the external test set. To demonstrate the practical applicability of the models in virtual screening, we screened an in-house data set with 3601 compounds, and 30 compounds were selected for further bioactivity assay. The assay results showed that 10 out of 30 compounds exerted significant BuChE inhibitory activities with IC50 values ranging from 0.32 to 22.22 μM, at which three new scaffolds as BuChE inhibitors were identified for the first time. To our best knowledge, this is the first report on BuChE inhibitors using machine learning approaches. The models generated from SVM and naive Bayesian approaches successfully predicted BuChE inhibitors. The study proved the feasibility of a new method for predicting bioactivities of ligands and discovering novel lead compounds.
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.forename: Ranyao
authors.initials: R
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Shengqian
authors.initials: S
authors.lastname: Yang
authors.forename: Ai-Lin
authors.initials: AL
authors.lastname: Liu
authors.forename: Guan-hua
authors.initials: GH
authors.lastname: Du
mesh_terms: D001185:Artificial Intelligence; D001499:Bayes Theorem; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D062126:Databases, Chemical; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D018697:Nootropic Agents / Q000737:chemistry*; D013329:Structure-Activity Relationship; D060388:Support Vector Machine; D014584:User-Computer Interface
chemical_list: D002800:Cholinesterase Inhibitors; D008024:Ligands; D018697:Nootropic Agents; D002091:Butyrylcholinesterase