Targeting D-alanine ligase from methicillin-resistant Staphylococcus aureus using natural compounds

Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a critical threat in healthcare and community settings. Meanwhile, the effectiveness of treatment is limited by vancomycin, which remains the only frontline drug against MRSA. The emergence of new strains of MRSA, along with the development of vancomycin-resistant S. aureus (VRSA), emphasises the need for alternative therapies. This study explores the use of natural compounds as a sustainable alternative to treat MRSA. The inhibition potential of natural compounds against D-alanine-d-alanine ligase, a key enzyme in the peptidoglycan synthesis, which belongs to the ATP Grasp Protein family. The ATP binding is responsible for the formation of the intermediate through enzyme catalysis. The 1252 molecules selected from the COCONUT database, with high predicted potency, low toxicity, and bioavailability, were subjected to virtual high-throughput screening (vHTS) against the ATP-binding site of the target protein. The two promising molecules were identified based on their orientations and interactions with ATP-binding residues. The selected protein-drug complexes were further evaluated by MD simulation to comprehend their effects under physiological conditions, followed by calculation of binding affinity using the MM-PBSA approach. The essential dynamics studies and MM-PBSA results suggested that CNP0475353 (ΔG = -98.78 kcal/mol) and CNP0263347 (ΔG = -10.63 kcal/mol) could act as potential inhibitors of Ddl by interacting with key ATP-binding residues. The study proposes that CNP0475353 and CNP0263347 may be explored for therapeutic potential against MRSA.