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Screening of Potential Lead Molecule as Novel MurE Inhibitor: Virtual Screening, Molecular Dynamics and In Vitro
Kunal Zaveri, Patnala Kiranmayi1
1Department of Biotechnology, Institute of Science, GITAM University, Vishakhapatnam, AP, India.
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.
Method:
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.
Conclusion:
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.
Insights
Researchers identified a novel MurE inhibitor with potential against multi-drug resistant Staphylococcus aureus infections. In vitro studies show promising antibacterial activity comparable to Vancomycin.
Area of Science:
- Biochemistry
- Drug Discovery
- Computational Chemistry
Background:
- Multi-drug resistant Staphylococcus aureus poses a significant challenge in treating nosocomial infections.
- The peptidoglycan biosynthesis pathway is a target for antibiotics, with MurE being a promising, yet underexplored, enzyme.
- MurE is crucial for peptidoglycan synthesis, making it a key target for novel antibacterial agents.
Purpose of the Study:
- To screen for potential MurE inhibitors using in silico methods.
- To evaluate the most promising lead molecule through in vitro assays.
Main Methods:
- Structure-based virtual screening targeting the MurE active site.
- Molecular dynamics simulations to assess complex stability.
- In vitro antibacterial activity and cytotoxicity assays.
Main Results:
- Virtual screening identified a lead molecule: (2R)-2-[[1-[(2R)-2-(benzyloxycarbonylamino) propanoyl] piperidine-4-carbonyl]amino]-5-guanidino-pentan.
- Molecular dynamics confirmed stable interactions of the lead molecule with MurE active site residues (Asp 406, Glu 460).
- In vitro studies demonstrated potent antibacterial activity (MIC 3.75 μg/mL) comparable to Vancomycin, with bactericidal effects (MBC 6.25 μg/mL) and acceptable cytotoxicity (IC50 40.06 μg/mL).
Conclusions:
- The identified lead molecule shows significant potential as a MurE inhibitor.
- This compound offers a promising therapeutic strategy against Staphylococcus aureus infections.
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