Molecular modeling and activity studies of the compounds active on the Escherichia Coli and Staphylococcus Aureus DNA gyrase B ATPase active site

For the design of new ligands, the use of computational methods and algorithms, such as HTVS (High Throughput Virtual Screening), docking-scoring and statistical methods such as ROC curves (Receiver Operating Characteristic curves) are among the popular methods used today. Generally, to use these methods, there must be X-Ray crystallography data or a homology model presenting macromolecule and ligand structures to study interactions. In alternative antimicrobial clinical treatment, the development of molecules based on DNA gyrase enzyme inhibition is important in cases such as Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) which not only have Gram - / Gram + distinction but also multiple drug resistance. Recently published information regarding E. coli and S. aureus, crystallographic data of DNA gyrase B (PDB id: 3G7E and 3G7B) give us an opportinity to use the methods of computer usage-based drug research in determining gram +/- selective inhibitor compounds. When we investigated the amino acid-ligand interactions of both E. coli and S. aureus, DNA gyrase B active sites with the help of crystallographic data and compared these interactions with the previous literature belong to DNA gyrase B ATPase inhibitors, we determined that some of the water molecules have major impact during these interactions in terms of selectivity. In this study, first, trial and test sets were prepared by consequent enrichment of the 5000 and 50000 ZINC databases with known E. coli and S. aureus DNA GyrB ATPase inihibitor molecules. Then, the trial set was evaluated, considering the contribution of water moleculoes on interactions, the trial set was screened on the active site of the ATPase E. coli and S. aureus DNA gyrases using crystallographic data and a HTVS method. The analysis of subset docking score led to the identification of novel interaction patterns. When these interaction paterns were screen over the test set similarly, 20 maximum scored compounds were determined and further tested against novobiocin standard with gel based E. coli and S. aureus. supercoiling assays, their activity and selectivity. The highest scoring N'-(1-naphthylcarbonyl)-2,1,3-benzothiadiazole-5-carbo-hydrazide structure showed a selective inhibition tword E. coli and S. aureus DNA gyrase B ATPases.