title: Bond-based bilinear indices for computational discovery of novel trypanosomicidal drug-like compounds through virtual screening.
abstract: Two-dimensional bond-based bilinear indices and linear discriminant analysis are used in this report to perform a quantitative structure-activity relationship study to identify new trypanosomicidal compounds. A data set of 440 organic chemicals, 143 with antitrypanosomal activity and 297 having other clinical uses, is used to develop the theoretical models. Two discriminant models, computed using bond-based bilinear indices, are developed and both show accuracies higher than 86% for training and test sets. The stochastic model correctly indentifies nine out of eleven compounds of a set of organic chemicals obtained from our synthetic collaborators. The in vitro antitrypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Both models show a good agreement between theoretical predictions and experimental results. Three compounds showed IC50 values for epimastigote elimination (AE) lower than 50 μM, while for the benznidazole the IC50 = 54.7 μM which was used as reference compound. The value of IC50 for cytotoxicity of these compounds is at least 5 times greater than their value of IC50 for AE. Finally, we can say that, the present algorithm constitutes a step forward in the search for efficient ways of discovering new antitrypanosomal compounds.
authors.affiliation: Centro de Estudio de Química Aplicada, Facultad de Química-Farmacia, Universidad Central "Marta Abreu" de Las Villas, Santa Clara, 54830, Villa Clara, Cuba; Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Universidad Central "Marta Abreu" de Las Villas, Santa Clara, 54830, Villa Clara, Cuba; Departament de Bioquímica i Biologia Molecular, Universitat de València, E-46100, Burjassot, Spain; Institut Universitari de Ciència Molecular, Universitat de València, Edifici d'Instituts de Paterna, P.O. Box 22085, E-46071, València, Spain. Electronic address: jacgarit@yahoo.es.
authors.forename: Juan Alberto
authors.initials: JA
authors.lastname: Castillo-Garit
authors.affiliation: Centro de Estudio de Química Aplicada, Facultad de Química-Farmacia, Universidad Central "Marta Abreu" de Las Villas, Santa Clara, 54830, Villa Clara, Cuba.
authors.forename: Oremia
authors.initials: O
authors.lastname: del Toro-Cortés
authors.affiliation: Centro para el Desarrollo de la Investigacion Cientifica (CEDIC) and Fundación Moisés Bertoni/Laboratorios Díaz Gill, Pai Perez 265 casi Mariscal Estigarribia, Asuncion, Paraguay.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Vega
authors.affiliation: Centro para el Desarrollo de la Investigacion Cientifica (CEDIC) and Fundación Moisés Bertoni/Laboratorios Díaz Gill, Pai Perez 265 casi Mariscal Estigarribia, Asuncion, Paraguay.
authors.forename: Miriam
authors.initials: M
authors.lastname: Rolón
authors.affiliation: Centro para el Desarrollo de la Investigacion Cientifica (CEDIC) and Fundación Moisés Bertoni/Laboratorios Díaz Gill, Pai Perez 265 casi Mariscal Estigarribia, Asuncion, Paraguay.
authors.forename: Antonieta
authors.initials: A
authors.lastname: Rojas de Arias
authors.affiliation: Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Universidad Central "Marta Abreu" de Las Villas, Santa Clara, 54830, Villa Clara, Cuba; Departament de Bioquímica i Biologia Molecular, Universitat de València, E-46100, Burjassot, Spain; Centro de Información y Gestión Tecnológica, Ministerio de Ciencia Tecnología y Medio Ambiente (CITMA), 65100, Ciego de Ávila, Cuba.
authors.forename: Gerardo M
authors.initials: GM
authors.lastname: Casañola-Martin
authors.affiliation: Departamento de Parasitología, Facultad de Farmacia, UCM, Pza. Ramón y Cajal s/n, 28040, Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Escario
authors.affiliation: Departamento de Parasitología, Facultad de Farmacia, UCM, Pza. Ramón y Cajal s/n, 28040, Madrid, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Gómez-Barrio
authors.affiliation: Enviromental and Computational Chemistry Group, Facultad de Química Farmacéutica, Universidad de Cartagena,Cartagena de Indias, Bolivar, Colombia.
authors.forename: Yovani
authors.initials: Y
authors.lastname: Marrero-Ponce
authors.affiliation: Institut Universitari de Ciència Molecular, Universitat de València, Edifici d'Instituts de Paterna, P.O. Box 22085, E-46071, València, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Torrens
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat de València, E-46100, Burjassot, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Abad
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016002:Discriminant Analysis; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013269:Stochastic Processes; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D014344:Trypanocidal Agents
keywords: Bond-based bilinear indices; In vitro cytotoxicity; LDA-assisted QSAR model; Trypanosomicidal; Virtual screening