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Streszczenie:
VanZ has crucial involvement in the modification of the bacterial peptidoglycan precursor and blocking its competence to bind with vancomycin and other related antibiotics. Hence targeting this protein can be an excellent option for combating the antibacterial resistance, particularly in the context of glycopeptide antibiotics like vancomycin. Hence, in this study, we have focused on the screening of 323 benzimidazole-based ligands for their possible interaction with the binding pocket of VanZ. The screening was based on the binding affinity values derived from molecular docking analysis. Furthermore, we had conducted an interacting amino acid analysis and we found six ligands that demand additional investigation. Consequently, we conducted molecular dynamics (MD) simulations using the optimal pose of VanZ to validate the stability of these VanZ–ligand complex and strengthen the consistency of the molecular docking results. Additionally, the pharmacological parameter was checked for all the six compounds. In summary, using the computational studies, we have successfully identified the putative candidates, which can be used for further in-vivo analyses. Our comprehensive approach can serve as a basis for the development of targeted compounds with enhanced efficacy against VanZ.

Słowa kluczowe:
Antibacterial Resistance, Glycopeptide Antibiotics, Drug screening, Ligands, 46 Molecular Docking, MD simulations

Streszczenie:
Toxin-antitoxin (TA) systems are small genetic elements which encode toxin proteins that interfere with vital cellular functions. PepA1 and PepG1 toxin proteins, known also as SprA1 and SprG1, are type I TA. In Staphylococcus aureus (S. aureus), their expression without the antitoxin counterparts (SprA1AS and SprF1), is lethal to the pathogen. Molecular Dynamics (MD) simulation was performed for PepA1 and PepG1 to understand their dynamic state, conformational changes, and their toxicity. The protein structures were constructed and used for MD simulation and the conformational changes, stability, flexibility, fluctuations, hydrophobicity, and role of their dynamic state on function prediction were studied extensively by GROMACS MD simulation analysis tools. In silico study indicated that the PepA1 and PepG1 proteins change their structural conformation from an open to closed state where PepA1 conformational changes were faster (10 ns) than PepG1 (20 ns) while PepG1 exerted more stability and flexibility than PepA1. According to SASA values, PepG1 is more hydrophobic than the PepA1 and forms fewer hydrogen bonds than PepA1. The in vivo study with PepA1 and PepG1 proteins provided evidence that both the conformation changes between the open and closed states and the amino acid sequence are crucial for peptide toxicity.

Słowa kluczowe:
Toxin-antitoxin system, Staphylococcus aureus, PepA1, PepG1, Molecular dynamics simulation, Cloning