Insight into DNA Gyrase Inhibition Using Quantitative Structure-Activity ‎Relationships and Structure-Based Drug Design Approaches

Abstract

The emergence of certain bacterial strains resistant ‎to antibiotics has become a major public health ‎problem, hence the need to develop new antibiotic ‎molecules. Bacterial DNA gyrase, a type II DNA ‎topoisomerase found in all bacteria is a proven ‎target for antibacterial chemotherapy. Our objective ‎is designing novel DNA Gyrase inhibitors using ‎Quantitative Structure-Activity Relationships and ‎Structure-Based Drug Design Approaches. We used ‎bioinformatics tools, biological databases like PDB ‎‎(Protein DataBank), Binding Databases and ‎software’s like, MarvinView, MarvinSketch, PyMOL, ‎AutoDockTools-1.5.6. The 3D crystal structure of ‎DNA Gyrase was extracted from PDB (code: 4DHU) ‎and we characterized the active site. Using 83 ‎compounds with different Ki were extracted from ‎Binding Databases, we built and validated a QSAR ‎Model (PLS regression) and we confirmed the ‎interesting correlation between predicted and ‎experimental Ki (R2=0,843). Four molecules were ‎chosen to be docked into DNA Gyrase active site ‎using AutoDockTools. The compound which has the ‎low Ki (Benzimidazole urea analogue 5) shows more ‎binding affinity with score value of ΔG= -8,6 kcal/mol ‎than the others compounds. So, it would be very ‎interesting to synthesis this promising compound ‎and to test in vitro its antibacterial properties.‎