Title:Molecular Modeling Studies of Novel Fluoroquinolone Molecules
VOLUME: 15 ISSUE: 2
Author(s):Tejeswara Rao Allaka, Naresh Kumar Katari*, Venkataramireddy Veeramreddy and Jaya Shree Anireddy*
Affiliation:Centre for Chemical Sciences and Technology, Institute of Science & Technology, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, Telangana 500 085, Department of Chemistry, GITAM School of Technology, GITAM University, HTP Campus, Rudraram, Medak, Telangana 502 329, Centre for Chemical Sciences and Technology, Institute of Science & Technology, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, Telangana 500 085, Centre for Chemical Sciences and Technology, Institute of Science & Technology, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, Telangana 500 085
Keywords:Pefloxacin hydrazones, molecular docking, Schrödinger software, DNA gyrase, fluoroquinolones,
protein.
Abstract:Background: Fluoroquinolones have been the centre of considerable scientific
and clinical interest due to their broad spectrum pharmacological activities.
Pefloxacin is an analogue of norfloxacin, which is a 3rd generation of fluoroquinolone
antibiotic similar to ciprofloxacin. Pefloxacin is used to treat a variety of bacterial
infections like respiratory tract, ear, nose and throat (ENT) infections, skin infections,
and urinary tract infections. Hydrazone as a pharmacophore unit that attracts
the medicinal chemists because of structure activity relationship (SAR) studies of
fluoroquinolones especially the functionality at C-3 position. Consequently, recognition
and development of potential ligands specifically for a protein target forms the
primary goal in drug discovery process. Among the different theoretical approaches
available, Gold and Glide are the molecular docking methods which find application
protein ligand studies. In the current study, the DNA gyrase of Staphylococcus aureus
has been used as the target protein to understand their possible interactions.
Methods: The crystal structure of DNA gyrase (topoisomerase II) was downloaded
from the Protein Data Bank (PDB ID: 2XCS, 3FOE) and molecular docking studies
were performed using the docking programs like Gold 3.2 (Genetic Algorithm for
Ligand Docking), Glide 5.0 (Grid Based Ligand Docking with Energetic). Melting
points were uncorrected and determined in open capillary tubes in a melting point
apparatus. TLC was performed on silica gel-G and spotting was done using iodine/
KMnO4 staining or UV-light. The following experimental procedures are representive
of the general procedures used to synthesize all compounds.
Results: The docking experiments of the title compounds with 2.1 Å crystal structure
of DNA gyrase 2XCS, 3FOE using Gold 3.2 and Glide 5.0 is carried out to understand
the binding interactions of the novel ligands with the protein, contributing for
antibacterial activity. The compounds in general exhibited good binding interactions
like H-bonding interaction and π-π interactions which stabilize the protein-ligand
complexes and responsible for good fitness scores in both the protocols.
Conclusion: In summary, a new series of novel pefloxacin hydrazones 5a-5n were
studied for their interactions with Staphylococcus aureus DNA gyrase protein by
Glide 5.0 and Gold 3.2 molecular docking protocols [PDB IDS: 2XCS, 3FOE].
Among the tested molecules, compound 5g exhibited a good Glide score value of –
7.73 and Glide energy −51.24 with emodel value of −66.16. The nice docking scores
of 5g, 5a, 8h, 5m and 5b revealed that these compounds are well accommodated on
the active site residues of DNA gyrase enzyme. From the docking study, we have
explored the probable binding mode and the binding pattern of compounds 5f, 5l, 5h,
5d, and 5n showed that they strongly interact with in the active site of Staphylococcus
aureus of DNA gyrase enzyme. From screening results it is found that compounds
having aromatic ring substituted with electron releasing groups are showing
potent docking scores and exhibited better fitness than reference compounds CPF
and CA4. An efficient combination of molecular modeling and biological activity
provided an insight into QSAR guide lines that could aid in further development and
optimization of the pefloxacin derivatives.
