Abstract
Legionella pneumophila is the causative organism for Legionnaires’ disease, pneumonia and life-threatening prosthetic valve endocarditis. MurB reductase, one of the important enzymes for biosynthesis of peptidoglycan, a component of cell wall, was identified as common drug target against bacterial pathogens causing infective endocarditis including Legionella pneumophila . MurB reductase with FAD acts as a cofactor and catalyzes the NADPH-dependent reduction of UDP-N-acetylenolpyruvylglucosamine (UDP-GlcNAcEP) to UDP-N-acetylmuramic acid. In the present study, 360 structural analogs of FAD were docked to MurB reductase of Legionella pneumophila using sequential protocol of Glide v5.7 implemented in virtual screening workflow of Maestro v9.2. Among seven leads were obtained through docking analysis, only lead1 (XPGscore -13.27Kcal/mol) was observed to have better binding affinity towards MurB reductase as compared to cofactor FAD (XPGscore -13.25Kcal/mol). Molecular level interactions of the MurB reductase- lead1 docking complex showed good correlation with MurB reductase- FAD complex. Further, molecular dynamic simulations for MurB reductase - lead1 docking complex were performed using Desmond v3.0 to shed light on natural dynamic of the docking complex in solution on different timescales. Molecular dynamic simulations of MurB reductase - lead1 complex showed stable nature of the docking interactions.
Highlights
Legionella pneumophila is significant cause of sporadic and epidemic community-acquired pneumonia (CAP) and nosocomial acquired pneumonia in both healthy and immune-suppressed hosts [1,2,3]
MurB reductase has a decisive role in formation of N-acetyl‐muramic acid subunit of peptidoglycan layer
MurB reductase of L. pneumophila was identified as a common drug target among bacterial pathogens causing infective endocarditis [16], it is worth mentioning to implement rational drug designing procedure to the MurB reductase for identifying novel lead molecules
Summary
Legionella pneumophila is significant cause of sporadic and epidemic community-acquired pneumonia (CAP) and nosocomial acquired pneumonia in both healthy and immune-suppressed hosts [1,2,3]. The mortality rate is the highest for bacteremic pneumococcal pneumonia and Legionnaires disease in patients with community-acquired pneumonia [4]. Prosthetic valve endocarditis is a life‐threatening microbial infection of the endocardial surface lining of the heart chambers and heart valves [11]. Cure for this patient needs prolonged parenteral antimicrobial therapy with either doxycycline or erythromycin, followed by prolonged oral therapy with these agents with duration of 6 to 17 months [10]. Levofloxacin (or other fluoroquinolone) or azithromycin were reported as current treatment of choice for Legionnaires’ disease [1].
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