A Molecular Docking and Dynamics Approach to Screen Potent Inhibitors Against Fosfomycin Resistant Enzyme in Clinical Klebsiella pneumoniae

ABSTRACT Klebsiella pneumoniae , BA6753 was cultured from a patient in the Clinical Microbiology Laboratory of Christian Medical College. K. pneumoniae, BA6753 has a multidrug resistance plasmid encoding novel FosA variant‐7, fosfomycin resistance enzyme. Minimal side effects and a wide range of bactericidal activity of fosfomycin have resulted in its expanded clinical use that prompts the rise of fosfomycin‐resistant strains. At present, there are no effective inhibitors available to conflict the FosA‐medicated fosfomycin resistance. To develop effective FosA inhibitors, it is crucial to understand the structural and dynamic properties of resistance enzymes. Hence, the present study focuses on the identification of potent inhibitors that can effectively bind to the fosfomycin resistance enzyme, thus predispose the target to inactivate by the second antibiotic. Initially, a series of active compounds were screened against the resistant enzyme, and the binding affinities were confirmed using docking simulation analysis. For efficient activity, the binding affinity of the resistance enzyme ought to be high with the inhibitor than the fosfomycin drug. Consequently, the enzyme‐ligand complex which showed higher binding affinity than the fosfomycin was employed for subsequent analysis. The stability of the top scoring enzyme‐ligand complex was further validated using molecular dynamics simulation studies. On the whole, we presume that the compound 19583672 demonstrates a higher binding affinity for the resistance enzyme comparing to other compounds and fosfomycin. We believe that further enhancement of the lead compound can serve as a potential inhibitor against resistance enzyme in drug discovery process. J. Cell. Biochem. 118: 4088–4094, 2017. © 2017 Wiley Periodicals, Inc.