title: Screening of Potential Lead Molecule as Novel MurE Inhibitor: Virtual Screening, Molecular Dynamics and In Vitro Studies.
abstract: BACKGROUND
  The prevalence of multi-drug resistance S. aureus is one of the most challenging tasks for the treatment of nosocomial infections. Proteins and enzymes of peptidoglycan biosynthesis pathway are one among the well-studied targets, but many of the enzymes are unexplored as targets. MurE is one such enzyme featured to be a promising target. As MurE plays an important role in ligating the L-lys to stem peptide at third position that is crucial for peptidoglycan synthesis.
  
  
  OBJECTIVE
  To screen the potential MurE inhibitor by in silico approach and evaluate the best potential lead molecule by in vitro methods.
  
  
  METHODS
  In the current study, we have employed structure based virtual screening targeting the active site of MurE, followed by Molecular dynamics and in vitro studies.
  
  
  RESULTS
  Virtual screening resulted in successful screening of potential lead molecule ((2R)-2-[[1-[(2R)- 2-(benzyloxycarbonylamino) propanoyl] piperidine-4-carbonyl]amino]-5-guanidino-pentan). The molecular dynamics of the MurE and Lead molecule complex emphasizes that lead molecule has shown stable interactions with active site residues Asp 406 and with Glu 460. In vitro studies demonstrate that the lead molecule shows antibacterial activity close to standard antibiotic Vancomycin and higher than that of Ampicillin, Streptomycin and Rifampicin. The MIC of lead molecule at 50μg/mL was observed to be 3.75 μg/mL, MBC being bactericidal with value of 6.25 μg/mL, cytotoxicity showing 34.44% and IC50 of 40.06μg/mL.
  
  
  CONCLUSIONS
  These results suggest ((2R)-2-[[1-[(2R)-2-(benzyloxycarbonylamino) propanoyl] piperidine-4-carbonyl]amino]-5-guanidino-pentan) as a promising lead molecule for developing a MurE inhibitor against treatment of S. aureus infections.
authors.forename: Kunal
authors.initials: K
authors.lastname: Zaveri
authors.affiliation: Department of Biotechnology, Institute of Science, GITAM University, Vishakhapatnam, AP, India.
authors.forename: Patnala
authors.initials: P
authors.lastname: Kiranmayi
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010880:Piperidines; D010453:Peptide Synthases; C049145:UDP-N-acetylmuramoylalanyl-D-glutamate-2,6-diaminopimelate ligase
keywords: Antibiotics; IC50; MIC; MRSA; molecular dynamics; peptidoglycan; virtual screening.