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  3. Bond-based bilinear indices for computational discovery of novel trypanosomicidal drug-like compounds through virtual screening

Bond-based bilinear indices for computational discovery of novel trypanosomicidal drug-like compounds through virtual screening

  • Eur J Med Chem. 2015:96:238-44. doi: 10.1016/j.ejmech.2015.03.063.
Juan Alberto Castillo-Garit 1,  Oremia del Toro-Cortés 2,  Maria C Vega 3,  Miriam Rolón 3,  Antonieta Rojas de Arias 3,  Gerardo M Casañola-Martin 4,  José A Escario 5,  Alicia Gómez-Barrio 5,  Yovani Marrero-Ponce 6,  Francisco Torrens 7,  Concepción Abad 8
Affiliations

Affiliations

  • 1 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.
  • 2 Centro de Estudio de Química Aplicada, Facultad de Química-Farmacia, Universidad Central "Marta Abreu" de Las Villas, Santa Clara, 54830, Villa Clara, Cuba.
  • 3 Centro para el Desarrollo de la Investigacion Cientifica (CEDIC) and Fundación Moisés Bertoni/Laboratorios Díaz Gill, Pai Perez 265 casi Mariscal Estigarribia, Asuncion, Paraguay.
  • 4 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.
  • 5 Departamento de Parasitología, Facultad de Farmacia, UCM, Pza. Ramón y Cajal s/n, 28040, Madrid, Spain.
  • 6 Enviromental and Computational Chemistry Group, Facultad de Química Farmacéutica, Universidad de Cartagena,Cartagena de Indias, Bolivar, Colombia.
  • 7 Institut Universitari de Ciència Molecular, Universitat de València, Edifici d'Instituts de Paterna, P.O. Box 22085, E-46071, València, Spain.
  • 8 Departament de Bioquímica i Biologia Molecular, Universitat de València, E-46100, Burjassot, Spain.
PMID: 25884114 DOI: 10.1016/j.ejmech.2015.03.063
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.

Keywords

Bond-based bilinear indices; In vitro cytotoxicity; LDA-assisted QSAR model; Trypanosomicidal; Virtual screening.

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