title: Prediction of Anti-inflammatory Plants and Discovery of Their Biomarkers by Machine Learning Algorithms and Metabolomic Studies.
abstract: Nonsteroidal anti-inflammatory drugs are the most used anti-inflammatory medicines in the world. Side effects still occur, however, and some inflammatory pathologies lack efficient treatment. Cyclooxygenase and lipoxygenase pathways are of utmost importance in inflammatory processes; therefore, novel inhibitors are currently needed for both of them. Dual inhibitors of cyclooxygenase-1 and 5-lipoxygenase are anti-inflammatory drugs with high efficacy and low side effects. In this work, 57 leaf extracts (EtOH-H2O 7 : 3, v/v) from Asteraceae species with in vitro dual inhibition of cyclooxygenase-1 and 5-lipoxygenase were analyzed by high-performance liquid chromatography-high-resolution-ORBITRAP-mass spectrometry analysis and subjected to in silico studies using machine learning algorithms. The data from all samples were processed by employing differential expression analysis software coupled to the Dictionary of Natural Products for dereplication studies. The 6052 chromatographic peaks (ESI positive and negative modes) of the extracts were selected by a genetic algorithm according to their respective anti-inflammatory properties; after this procedure, 1241 of them remained. A study using a decision tree classifier was carried out, and 11 compounds were determined to be biomarkers due to their anti-inflammatory potential. Finally, a model to predict new biologically active extracts from Asteraceae species using liquid chromatography-mass spectrometry information with no prior knowledge of their biological data was built using a multilayer perceptron (artificial neural networks) with the back-propagation algorithm using the biomarker data. As a result, a new and robust artificial neural network model for predicting the anti-inflammatory activity of natural compounds was obtained, resulting in a high percentage of correct predictions (81 %), high precision (100 %) for dual inhibition, and low error values (mean absolute error = 0.3), as also shown in the validation test. Thus, the biomarkers of the Asteraceae extracts were statistically correlated with their anti-inflammatory activities and can therefore be useful to predict new anti-inflammatory extracts and their anti-inflammatory compounds using only liquid chromatography-mass spectrometry data.
authors.affiliation: AsterBioChem Research Team, Laboratory of Pharmacognosy, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Daniela Aparecida
authors.initials: DA
authors.lastname: Chagas-Paula
authors.affiliation: AsterBioChem Research Team, Laboratory of Pharmacognosy, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Tiago Branquinho
authors.initials: TB
authors.lastname: Oliveira
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland.
authors.forename: RuAngelie
authors.initials: R
authors.lastname: Edrada-Ebel
authors.affiliation: AsterBioChem Research Team, Laboratory of Pharmacognosy, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Fernando Batista
authors.initials: FB
authors.lastname: Da Costa
mesh_terms: D000465:Algorithms; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification*; D015415:Biomarkers / Q000032:analysis*; D002851:Chromatography, High Pressure Liquid; D000069550:Machine Learning; D013058:Mass Spectrometry; D055432:Metabolomics; D010946:Plants, Medicinal / Q000737:chemistry*
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers