Discovery of new Gyrase β inhibitors via structure based modeling

Gyrase B is an essential enzyme in the prokaryotes which became an attractive target for antibacterial agents. In our study, we implemented a wide range of docking configurations to dock 120 inhibitors into the in the ATP- binding pocket of Gyrase B enzyme (PDB code: 4GEE). LigandFit docking engines and six scoring functions were utilized in the study. Furthermore, the ligands were docked in their ionized and unionized forms into the hydrous and anhydrous binding pocket. We used docking-based Comparative Intermolecular Contacts Analysis (db-CICA) which is a novel methodology to validate and identify the optimal docking configurations. Three docking configurations were found to achieve self-consistent db-CICA models. The resulting db-CICA models were used to construct corresponding pharmacophoric models that were used to screen the National Cancer Institute (NCI) list of compounds. In-vitro study represents antibacterial activities for twelve hit molecules with the most active having IC₅₀ of 20.9 μM.