Insight into DNA Gyrase inhibition using quantitative structure-Activity relationships and structure-based drug design approaches

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 StructureActivity 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.

Evaluation of Dimethylformamide (DMF) as an Organic Modifier in Hydrophobicity Index (R[m]) Determination

PURPOSE: Ideal behaviour of mixtures of organic modifier and water is reflected by a linear relationship between refractive index and fraction of organic modifier in the mixture. This study was carried out to investigate dimethylformamide (DMF) as an organic modifier in hydrophobicity index (Rm) determination. METHOD: We quantitatively evaluated the problem of partial miscibility of phases associated with the reversed phase thin layer chromatographic (RPTLC) system; using liquid paraffin as stationary phase and acetone/water mixtures as mobile phase. Ideality of behaviour of acetone/water mixtures was investigated by refractive index measurements. R[m] values of compounds were determined using mixtures of acetone and water as mobile phase. RESULTS: DMF/water mixture behaved ideally across the whole concentration range investigated (0-100 percent) while acetone/water mixture deviated from ideal behaviour when the concentration of acetone in the mixture was 80 percent. DMF also gave a better extrapolation of R[m] value from linear regression of partition data than acetone for bezafibrate used as a test-drug molecule. CONCLUSION : DMF is a better organic modifier than acetone in this RPTLC system. These findings could be extended to drug-receptor and drug design studies. The use of dimethylformamide (DMF) in preference to acetone as organic modifier is proposed in this study