Combination of Molecular Modeling and Quantum Mechanical Studies to Understand Quinolone Resistance Mechanism of Mycobacterium Tuberculosis

The increasing emergence of multiple and extensive drug resistant tuberculosis poses a significant threat to effective control of tuberculosis (TB) globally. Resistance is a serious threat in the battle against the treatment and eradication of Tuberculosis. The continuing rise in tuberculosis incidence and the problem of drug resistance strains have prompted the research on developing new drug candidates and understanding the mechanism of drug resistance. Fluoroquinolone resistance poses a significant threat to the effective control of Multiple Drug Resistant Tuberculosis (MDR-TB) and Extensive Drug Resistant Tuberculosis (XDR-TB). Ciprofloxacin, Levoflaxacin, Gatifloxacin, and Moxifloxacin represent the important class of fluoroquinolones that inhibit mycobacterial DNA gyrase enzyme. We used combination of molecular modeling and quantum mechanical calculations to understand a compare the binding affinities and electronic structural properties of fluoroquinolones. Molecular docking studies were performed on DNA gyrase, with quinolones and the binding affinities were ranked with scoring functions. Three different docking modes were used to compare the binding affinities; moxifloxacin showed high binding affinity in all the three docking modes and showed hydrogen bonding and hydrophobic interactions with the active site of the target protein. Semi-empirical quantum mechanical Hartree-Fock formalism is used to understand the electronic structural properties of quinolones. Reactivity of the molecules was compared from electronic structural perspective; moxifloxacin showed high reactivity with more number of delocalized electrons.