title: In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids.
abstract: Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs) represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery.
authors.affiliation: Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia. birgit.viira@gmail.com.|Bioorganic and Medicinal Chemistry Team, UMR 7509 CNRS-Universit&#233; de Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, Strasbourg F-67087, France. birgit.viira@gmail.com.|Laboratoire de Chemoinformatique, UMR7140 CNRS-Universit&#233; de Strasbourg, 1 rue Blaise Pascal, Strasbourg F-67000, France. birgit.viira@gmail.com.
authors.forename: Birgit
authors.initials: B
authors.lastname: Viira
authors.affiliation: Bioorganic and Medicinal Chemistry Team, UMR 7509 CNRS-Universit&#233; de Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, Strasbourg F-67087, France. t.gendron@ucl.ac.uk.
authors.forename: Thibault
authors.initials: T
authors.lastname: Gendron
authors.affiliation: Bioorganic and Medicinal Chemistry Team, UMR 7509 CNRS-Universit&#233; de Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, Strasbourg F-67087, France. don.antoine.lanfranchi@gmail.com.
authors.forename: Don Antoine
authors.initials: DA
authors.lastname: Lanfranchi
authors.affiliation: Antiparasitic Chemotherapy, Faculty of Pharmacy, BioCIS, UMR 8076 CNRS-Universit&#233; Paris-Sud, Rue Jean-Baptiste Cl&#233;ment, Chatenay-Malabry F-92290, France. sandrine.cojean@u-psud.fr.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cojean
authors.affiliation: Laboratoire de Chemoinformatique, UMR7140 CNRS-Universit&#233; de Strasbourg, 1 rue Blaise Pascal, Strasbourg F-67000, France. dhorvath@unistra.fr.
authors.forename: Dragos
authors.initials: D
authors.lastname: Horvath
authors.affiliation: Laboratoire de Chemoinformatique, UMR7140 CNRS-Universit&#233; de Strasbourg, 1 rue Blaise Pascal, Strasbourg F-67000, France. g.marcou@unistra.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Marcou
authors.affiliation: Laboratoire de Chemoinformatique, UMR7140 CNRS-Universit&#233; de Strasbourg, 1 rue Blaise Pascal, Strasbourg F-67000, France. varnek@unistra.fr.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Varnek
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, Antwerp B-2610, Belgium. louis.maes@ua.ac.be.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.affiliation: Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia. uko.maran@ut.ee.
authors.forename: Uko
authors.initials: U
authors.lastname: Maran
authors.affiliation: Antiparasitic Chemotherapy, Faculty of Pharmacy, BioCIS, UMR 8076 CNRS-Universit&#233; Paris-Sud, Rue Jean-Baptiste Cl&#233;ment, Chatenay-Malabry F-92290, France. philippe.loiseau@u-psud.fr.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Loiseau
authors.affiliation: Bioorganic and Medicinal Chemistry Team, UMR 7509 CNRS-Universit&#233; de Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, Strasbourg F-67087, France. elisabeth.davioud@unistra.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Davioud-Charvet
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D030024:Curcuma / Q000737:chemistry; D057225:Data Mining; D015195:Drug Design; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D010936:Plant Extracts
keywords: Michael addition; Plasmodium falciparum; antimalarial; curcuminoid; in silico; quantitative structure-activity relationships (QSAR); thioredoxin reductase