Discovery and development of new antibacterial agents is a challenging task for the pharmaceutical industry. With current clinical practice and widespread use of antibacterial agents, the emergence of bacterial resistance cannot be avoided. Of concern is the fact that there is an emergence of strains resistant to several antibacterial agents simultaneously, of which ESKAPE organisms (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) are the most important. For this reason, the key challenge in development is the search for new structurally diverse active substances with new mechanisms of action and the use of new therapeutic targets.
One of the most important targets in the development of antibacterial agents is the bacterial cell wall and the enzymes involved in its biosynthesis. Because of their essential role in bacterial cells, enzymes MurA and MurB are attractive targets in the development of novel active substances. For both enzymes, several structurally different compounds with inhibitory activities have been described in the literature. Due to the poor physicochemical properties of these compounds, only phosphomycin which inhibits the action of MurA has reached the clinical use.
Modern computer technology enables quicker discovery and development of new active substances, so in our work, we have used state-of-the-art ligand-based virtual screening methods. We have worked with in silico tools that are tailored to run on graphic cards and have allowed us to use the multi-million compound library for virtual screening.
This masters' thesis describes the use of ROCS and FastROCS software and compares their use on a smaller and more extensive library of compounds. The two programs work similarly, identifying the same scaffolds among the results of the ligand-based virtual screening, regardless of the amount of data used. By using a larger library of compound, we get a better fit with selected queries compared to a smaller base. The chemical diversity of the scaffolds is higher within the results of the smaller library of compounds because there is a higher proportion of the unique parts of the structures than within results of the larger library. The best-evaluated compounds are proposed for further biological testing of their inhibition of MurA and MurB.
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