IN SILICO DESIGN AND IDENTIFICATION OF POTENTIAL D-ALA: D-ALA LIGASE INHIBITORS AGAINST STAPHYLOCOCCUS AUREUS
DOI:
https://doi.org/10.22159/ijap.2025v17i4.54510Keywords:
SADDL, Molecular docking, MM-GBSA, MD simulation, Glide score, RMSD, antibacterial agent, Staphylococcus aureus, Protein–ligand interaction, Mg²⁺ coordinationAbstract
Objective: This study aimed to identify potent inhibitors of Staphylococcus aureus D-alanine: D-alanine ligase (SADDL), a key enzyme in bacterial cell wall synthesis, by designing and evaluating a series of hydrazine carbothioamide derivatives. These scaffolds were selected due to their previously reported antimicrobial activity and potential for structural optimization.
Methods: Nine novel hydrazine carbothioamide derivatives were rationally designed and computationally assessed using an integrated in silico workflow. Molecular docking was performed against the SADDL active site (PDB ID: 2I80) using the Glide module to estimate binding affinity through Glide score, Extra-precision Hydrogen-bonding (XP H-bonding), van der Waals, Coulombic energy, and E-model scores. Binding free energies (ΔG_bind) were calculated using Molecular Mechanics-General Born Surface Area (MM-GBSA) to refine the ranking. To validate stability, a 100 ns Molecular Dynamics (MD) simulation using Desmond was conducted for the top-ranked compound, with Root mean Square Deviation (RMSD), Root mean Square Fluctuation (RMSF), and protein–ligand interaction analysis.
Results: Compound 1 demonstrated the best binding affinity with a Glide score of-11.11 kcal/mol and ΔG_bind of-96.06 kcal/mol, outperforming the co-crystallized ligand (-9.88 kcal/mol and- 59.98 kcal/mol). It exhibited strong van der Waals (-27.87kcal/mol) and Coulombic (-207.11kcal/mol) energies, as well as significant XP H-bonding (-3.25kcal/mol). Compound 6 and 8 also showed favorable interactions. MD simulations confirmed the stable binding of Compound 1 up to 60 ns, with consistent RMSD and low RMSF. Key residues involved included Ser150, Ser151, Glu187, and Lys215. Coordination with Mg²⁺ via Glu270, Asp257, and Ser150 further enhanced binding stability.
Conclusion: Compound 1 emerged as a promising SADDL inhibitor with strong and stable binding, suggesting its potential as a lead antibacterial agent. Further in vitro and in vivo studies are warranted.
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