title: Novel coumarin-based tyrosinase inhibitors discovered by OECD principles-validated QSAR approach from an enlarged, balanced database.
abstract: The present work is devoted to the development and application of a multi-agent Quantitative Structure-Activity Relationship (QSAR) classification system for tyrosinase inhibitor identification, in which the individual QSAR outputs are the inputs of a fusion approach based on the voting mechanism. The individual models are based on TOMOCOMD-CARDD (TOpological Molecular COMputational Design-Computer Aided Rational Drug Design) atom-based bilinear descriptors and Linear Discriminant Analysis (LDA) on a novel enlarged, balanced database of 1,429 compounds within 701 greatly dissimilar molecules presenting anti-tyrosinase activity. A total of 21 adequate models are obtained taking into account the requirements of the Organization for Economic Cooperation and Development (OECD) principles for QSAR validation and present global accuracies (Q) above 84.50 and 79.27% in the training and test sets, respectively. The resulted fusion system is used for the in silico identification of synthesized coumarin derivatives as novel tyrosinase inhibitors. The 7-hydroxycoumarin (compound C07) shows potent activity for the inhibition of monophenolase activity of mushroom tyrosinase giving a value of inhibition percentage close to 100% in vitro assays, by means of spectrophotometric analysis. The current report could help to shed some clues in the identification of new chemicals that inhibit tyrosinase enzyme, for entering in the pipeline of drug discovery development.
authors.affiliation: Unit of Computer-Aided Molecular Biosilico Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Central University of Las Villas, Santa Clara, Villa Clara, 54830, Cuba.
authors.forename: Huong
authors.initials: H
authors.lastname: Le-Thi-Thu
authors.forename: Gerardo M
authors.initials: GM
authors.lastname: Casañola-Martín
authors.forename: Yovani
authors.initials: Y
authors.lastname: Marrero-Ponce
authors.forename: Antonio
authors.initials: A
authors.lastname: Rescigno
authors.forename: Luciano
authors.initials: L
authors.lastname: Saso
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.forename: Francisco
authors.initials: F
authors.lastname: Torrens
authors.forename: Concepción
authors.initials: C
authors.lastname: Abad
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D017076:Computer-Aided Design; D003374:Coumarins / Q000737:chemistry*; D016208:Databases, Factual; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008024:Ligands; D008962:Models, Theoretical; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D012107:Research Design
chemical_list: D003374:Coumarins; D004791:Enzyme Inhibitors; D008024:Ligands; C030123:coumarin; D014442:Monophenol Monooxygenase
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