title: ANN multiplexing model of drugs effect on macrophages; theoretical and flow cytometry study on the cytotoxicity of the anti-microbial drug G1 in spleen.
abstract: Multiplexed biological assays provide multiple measurements of cellular parameters in the same test. In this work, we have trained and tested an Artificial Neural Network (ANN) model for the first time, in order to perform a multiplexing prediction of drugs effect on macrophage populations. In so doing, we have used the TOPS-MODE approach to calculate drug molecular descriptors and the software STATISTICA to seek different ANN models such as: Linear Neural Network (LNN), Radial Basis Function (RBF), Probabilistic Neural Networks (PNN) and Multi-Layer Perceptrons (MLP). The best model found was the LNN, which correctly classified 8258 out of 9000 (Accuracy = 93.0%) multiplexing assay endpoints of 7903 drugs (including both training and test series). Each endpoint corresponds to one out of 1418 assays, 36 molecular or cellular targets, 46 standard type measures, in two possible organisms (human and mouse). Secondly, we have determined experimentally, for the first time, the values of EC(50) = 11.41 μg/mL and Cytotoxicity = 27.1% for the drug G1 over Balb/C mouse spleen macrophages using flow cytometry. In addition, we have used the LNN model to predict the G1 activity in 1265 multiplexing assays not measured experimentally (including 152 cytotoxicity assay endpoints). Both experimental and theoretical results point out a low macrophage cytotoxicity of G1. This work breaks new ground for the 'in silico' multiplexing screening of large libraries of compounds. The results obtained are very significant because they complement the immunotoxicology studies of this important anti-microbial/anti-parasite drug.
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, CP15782 Santiago de Compostela, Spain.
authors.forename: Esvieta
authors.initials: E
authors.lastname: Tenorio-Borroto
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Peñuelas Rivas
authors.forename: Juan C
authors.initials: JC
authors.lastname: Vásquez Chagoyán
authors.forename: Nilo
authors.initials: N
authors.lastname: Castañedo
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Prado-Prado
authors.forename: Xerardo
authors.initials: X
authors.lastname: García-Mera
authors.forename: Humberto
authors.initials: H
authors.lastname: González-Díaz
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000633:toxicity*; D002478:Cells, Cultured; D062126:Databases, Chemical; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008962:Models, Theoretical; D016571:Neural Networks, Computer; D012372:ROC Curve
chemical_list: D000890:Anti-Infective Agents