Thursday , 3 December 2020

In-Silico Structure-Activity Relationship and Molecular Docking Study of Levofloxacin and its Mono substitted Analogues against the Escherichia coli DNA Gyrase

O.A Durojaye*, U. I Njoku, S. Cosmas, E. N Akpan, M. M Ganyam
University of Nigeria, Nsukka.

 A B S T R A C T
Background: Escherichia coli is one of the most frequent causes of many common bacterial infections, including cholecystitis, bacteremia, cholangitis, urinary tract infection (UTI), traveler’s diarrhea, and other clinical infections such as neonatal meningitis and pneumonia. Levofloxacin, a chiralfluorinated carboxyquinoloneis used to treat a variety of bacterial infections. This medication belongs to a class of drugs known as quinolone antibiotics. It functions by inhibiting the DNA gyrase and topoisomerase IV of both Gram-positive and Gram-negative bacteria. Materials and Methods: Molecular docking study was carried out on four analogous structurally diverse levofloxacin against Escherichia coli DNA Gyrase using the Autodock Vina software. Extensive structure activity relationship study was also carried out with these molecules.  The physiochemical analysis, lipophilicity, solubility, pharmacokinetics and Lipinski drug likeness of levofloxacin and its mono substituted analogues were evaluated. These molecules were designed by substituting the fluorine (F) attachment of the levofloxacin with CH3, OH, NH2 and C=O groups. The scoring function (empirical binding free energy) and hydrogen bond formation was used to estimate the inhibitory effect of the protein-ligand complex. Results: The binding energy of levofloxacin was -7.2kcal/ mol. The free binding energies of the CH3, OH, NH2 and C=O analogues of levofloxacin were -7.7, -6.5, -6.8 and -6.4Kcal/mol respectively. Levofloxacin also formed 4 hydrogen bonds with the Escherichia coli DNA Gyrase while it’s CH3, OH, NH2 and C=O analogues formed 8, 8, 13, and 2 hydrogen bonds respectively. All other mono substituted analogues except the CH3 analogue of levofloxacin, showed slightly higher values than the non substituted levofloxacin. The CH3, OH and NH2 analogues also formed more hydrogen bonds with the target enzyme than levofloxacin. The lower free binding energy value (more negative value) displayed by the CH3 analogue means it show a better antimicrobial activity than levofloxacin. The higher number of hydrogen bonds formed by the CH3 and NH2 analogues also indicates a higher binding affinity with the target enzyme. The two analogues do not cross the blood brain barrier (BBB). This also shows that they cannot cause problem to the brain. Conclusion: These results indicated that the CH3 and NH2 analogues may be better antimicrobial agents. Synthesis and pre-clinical studies of these mono substituted derivatives with Escherichia coli DNA Gyrase is recommended in order to confirm their new potentials as better antimicrobial agents than the unsubstituted analogue.
Keywords: Docking, Levofloxacin, Escherichia coli DNA Gyrase, Pharmacokinetics, Blood Brain Barrier.

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