The discovery of antibacterial agents is an important turning point for mankind. Unfortunately, soon after the discovery of the first antibacterial agents, bacteria became resistant. The number of resistant bacteria is constantly increasing, so today we are facing a big problem. The European Commission estimates that 33,000 people die each year in Europe from infection with bacteria resistant to antibacterial agents. Gram negative bacteria are of greater concern because no agents with new mechanisms of action have been developed against them for several decades. One of the main reasons for the lack of development of new antibacterial agents is the lack of lead compounds, but of course the complexity of development also contributes, along with the high costs and poor return on investment. In the fight against bacterial resistance, reduced unnecessary use of antibacterial agents and the discovery and development of new antibacterial agents are recommended. One of the interesting targets for the development of new antibacterial agents is DNA gyrase. Currently, the best-known inhibitors of DNA gyrase are quinolones. These are broad-spectrum antibacterial agents that bind to DNA and DNA gyrase and thus stabilize the complex. Unfortunately, the resistance of bacteria to fluoroquinolones is constantly increasing, so we are looking for new DNA gyrase inhibitors.
During the master's thesis, we used computational methods to search for new allosteric DNA gyrase inhibitors. A known allosteric DNA gyrase inhibitor served as the starting compound. We divided the work into two parts. First, we performed a virtual screening based on the ligand structure, and later based on the enzyme-ligand structure. In the ligand-based screening, the similarity of the compounds from the compound library was determined to the known DNA gyrase inhibitor. The similarity was evaluated based on the functional groups and the surface/shape of the molecule, followed by the electrostatic similarity. The results of each solution were analyzed and presented in the master 's thesis. We also selected some structurally different compounds, ordered them, and tested their inhibitory activity on Escherichia coli DNA gyrase in an in vitro system. The test showed that the selected compounds at concentrations of 10 and 100 µM unfortunately did not inhibit the action of E. coli DNA gyrase.
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