Bacterial FabH inhibitors: from bits to thewet‐lab

Bacterial FabH inhibitors: from bits to thewet‐lab

Ciencias técnicas

Ciencias de la Educación

Antibiotic resistance has increased over the past two decades. Since only two new classes of antibiotics have been introduced over the past 30 years, new approaches for the discovery of novel antibacterials are required and innovative strategies will be necessary to identify novel and effective candidates. Related to this problem, the exploration of bacterial targets that remain unexploited by the current antibiotics in clinical use is required. One of such targets is the ß-ketoacyl-acyl carrier protein synthase III (FabH). In this thesis is proposed a combined ligand- and structure-based modeling approach for the virtual screening of databases of chemical compounds to discover novel FabH inhibitors. We describe the implementation and validation of our own QSAR modeling framework based on the combination of feature selection using Genetic Algorithms, Bagged Trees and Features Ranking and the classifiers Adaboost, Least-Square Support Vector Machines and Linear Discriminant Analysis. Special emphasis is make in the analysis of our recently introduced GA(M)E-QSAR methodology. We compile a set of 296 known FabH inhibitors from the literature that is employed to derive classification models which are thoroughly validated. All the classification models showed high fitting, robustness and generalization capabilities. However, when the models are validated in the context of a virtual screening experiment their limitations arise. For this reason, the final ligand-based virtual screening tool is an ensemble built from the best performing QSAR models. This ensemble model is capable of achieving good initial enrichment of actives in a dataset composed of 24 known inhibitors and 38616 decoy molecules. Despite the good results obtained with the ligand-based strategy, this approach neglects the influence of the receptor structure. To overcome this difficulty an extensive Molecular Dynamics study of FabH was performed. The results of the Molecular Dynamics simulations ...

Pérez Castillo, Yunierkis Nowé, Ann (Director)

Editorial Universitaria

2013

Cuba, Ministerio de Educación Superior

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