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Title: Understanding DNA GyraseB ATPase inhibition in the light of structure and ligand-based modelling techniques.
Other Titles: Het verklaren van DNA GyraseB ATPase inhibitie met behulp van structuur en ligand gebaseerde modelbouw technieken.
Authors: Saiz Urra, Liane; S0208606
Issue Date: 12-Dec-2012
Abstract: The alarming antibiotic resistance spread is the main reasonthat demands the continued investigation to search for new antimicrobialagents. DNA Gyrase is a validated antibacterial target that can be used forthis purpose. This essential prokaryotic type II topoisomerase enzyme isinvolved in DNA replication, transcription and recombination by introducingnegative supercoiling in DNA at the expenses of ATP hydrolysis. It consists of twosubunits Gyrase A (GyrA) which participate in DNA breakage and reunion and twosubunits Gyrase B (GyrB) that catalyze the hydrolysis of ATP. The interest inthe Gyrase B (GyrB) subunit is growing because of persistent resistanceproblems of GyrA inhibitors.In this thesis, research on DNA Gyrase B ATPase inhibitionwas performed by using both structure and ligand-based modelling techniques.First, the antibiotic crisis, the biological function of the gyrase enzyme aswell as the outlook on the theoretical background of different target andligand-based modelling methods are briefly described. In addition, a review ofthe state of the art of the GyrB inhibitors and the reports of modellingtechniques used so far to address this topic are presented. Molecular dynamic simulations were used to explore theconformational changes of the protein in bound and free state in the endeavourof understanding the role of flexible loops. Furthermore, force field basedfree energy calculation techniques, like computational alanine scanning andenergy decomposition at an atomic level were used to study the interaction ofknown inhibitors with residues of the ATP binding site. The study suggestedthat both techniques could provide valuable information about the possiblebinding mode when studying to-be-determined binders.Molecular recognition at DNA gyrase B enzyme–inhibitorbinding interface was rationalized by means of molecular docking and furtherrefinement of the obtained poses with short Molecular Dynamic simulations whichenabled the use of rescoring schemes based on MM-PB(GB)SA and Zapbind. AlthoughMM-PBSA outperformed the rest of the methods, limitations in getting accurateresults when using this method in virtual screening to search for GyrBinhibitors were discussed.In an effort to overcome these limitations, ligand-basedQuantitative-Structure-Activity-Relationship models for binary classification(active/inactive compounds) were built. Adaboost ensembles of 1-feature LinearDiscriminant Analysis models were generated during <span style="mso-bidi-font-weight:bold">Genetic Algorithms (GA) iterations as well as Adaboost and VotingMeta-Ensembles. In addition, Least Squares–Support Vector Machine involving GAfor the selection of the features (GA-LS-SVM) were explored using moleculardescriptors that encoded diverse structural information. The study revealedthat despite these models lack a straightforward interpretation of theinfluence of the structural encoded information in the biological activity;they outperformed the target based approaches when it comes to correlatingstructural information with experimental enzyme activity data.Moreover, information from more simple regression models andmolecular docking has been used to guide the design of new analogues with theaim to improve the potency profile. Last but not least, a ‘wet’ experimentalscreening was performed by means of a supercoiling assay to a set of thirteen 2-and 3-carboxamide chromone like compounds showing a common chromone moiety withquercetin, a proven GyrB inhibitor. Two out of the thirteen analogues showedweak supercoiling inhibition and some modifications were proposed based onmolecular docking binding mode prediction to enhance potency and selectivitytoward bacterial GyrB.Despite the limitations of the modelling techniques exploredalong this work, we consider they can be combined and used carefully to addressthe search for new GyrB inhibitors. 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Publication status: published
KU Leuven publication type: TH
Appears in Collections:Department of Pharmaceutical & Pharmacological Sciences - miscellaneous
Medicinal Chemistry

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