Conformation-dependent QSAR approach for the prediction of inhibitory activity of bromodomain modulators.
Epigenetic drug discovery is a promising research field with growing interest in the scientific community, as evidenced by the number of publications and the large amount of structure-epigenetic activity information currently available in the public domain. Computational methods are valuable tools to analyse and understand the activity of large compound collections from their structural information. In this manuscript, QSAR models to predict the inhibitory activity of a diverse and heterogeneous set of 88 organic molecules against the bromodomains BRD2, BRD3 and BRD4 are presented. A conformation-dependent representation of the chemical structures was established using the RDKit software and a training and test set division was performed. Several two-linear and three-linear QuBiLS-MIDAS molecular descriptors ( www.tomocomd.com ) were computed to extract the geometric structural features of the compounds studied. QuBiLS-MIDAS-based features sets, to be used in the modelling, were selected using dimensionality reduction strategies. The multiple linear regression procedure coupled with a genetic algorithm were employed to build the predictive models. Regression models containing between 6 to 9 variables were developed and assessed according to several internal and external validation methods. Analyses of outlier compounds and the applicability domain for each model were performed. As a result, the models against BRD2 and BRD3 with 8 variables and the model with 9 variables against BRD4 were those with the best overall performance according to the criteria accounted for. The results obtained suggest that the models proposed will be a good tool for studying the inhibitory activities of drug candidates against the bromodomains considered during epigenetic drug discovery.
a Instituto de Química, Universidad Nacional Autónoma de México (UNAM) , Ciudad de México , México.|b Escuela de Sistemas y Computación , Pontificia Universidad Católica del Ecuador Sede Esmeraldas (PUCESE) , Esmeraldas , Ecuador.|c Grupo de Investigación de Bioinformática , Universidad de las Ciencias Informáticas (UCI) , La Habana , Cuba.
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García-Jacas
a Instituto de Química, Universidad Nacional Autónoma de México (UNAM) , Ciudad de México , México.
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Martinez-Mayorga
d Grupo de Medicina Molecular y Traslacional (MeM&T) , Universidad San Francisco de Quito (USFQ) , Quito , Ecuador.|e Grupo de Investigación Ambiental (GIA) , Fundación Universitaria Tecnológica de Comfenalco , Bolívar , Colombia.
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Marrero-Ponce
f Departamento de Farmacia , Universidad Nacional Autónoma de México (UNAM) , Ciudad de México , México.
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Medina-Franco
D018797:Cell Cycle Proteins; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects; D015233:Models, Statistical; D008968:Molecular Conformation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000092468:Bromodomain Containing Proteins
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human
3D molecular descriptors; Applicability domain; QSAR; QuBiLS-MIDAS; TOMOCOMD-CARDD; bromodomains; epigenetic drug discovery