• Rajendra Choure
• Nidhin Suresh
• Yash Pawar
• Sarang Lobhi
• Rupendra Jadhav

Abstract : The rising threat of antimicrobial resistance (AMR) in pathogens like methicillin- resistant Staphylococcus aureus (MRSA) demands novel therapeutic strategies. Anti-virulence therapy, which targets virulence factors instead of cell viability, offers a promising approach to mitigate the selective pressure for resistance. Sortase A (SrtA), a membrane-associated transpeptidase that anchors key virulence factors to the cell wall of S. aureus, is a primary anti-virulence target. This study employs an in silico approach, integrating molecular docking and 150 ns molecular dynamics (MD) simulations, to evaluate the chickpea peptide CaNCR63 as a potential inhibitor against S. aureus SrtA (PDB ID: 1T2W). Docking analysis predicted a favorable binding orientation for CaNCR63 within the catalytic groove of SrtA. However, subsequent 150 ns MD simulations, performed to validate this pose, revealed that the complex was transient and ultimately unstable. The peptide failed to remain anchored and dissociated from the active site after approximately 110 ns. A detailed analysis of the trajectory provided a clear molecular explanation for this instability. Despite forming geometrically favorable, near-linear hydrogen bonds with the active site, the peptide’s high internal flexibility and likely unfavorable desolvation energetics were sufficient to overcome these interactions, leading to dissociation. These findings establish that while CaNCR63 is a promising hit from docking, it is an unstable, transient binder, not a potent inhibitor. This study highlights the critical importance of MD simulations in validating static docking hits and provides a robust molecular framework for the rational optimization of the CaNCR63 scaffold for the development of novel anti-virulence therapeutics

Antimicrobial Resistance (AMR), Staphylococcus aureus, Sortase A (SrtA), Anti-virulence, Peptide Inhibitor, Molecular Dynamics Simulation, Molecular Docking

"In Silico Elucidation of the Inhibitory Mechanism of Chickpea Peptide CaNCR63 against Staphylococcus aureus Sortase A", International Journal of Emerging Technologies and Innovative Research (www.jetir.org), ISSN:2349-5162, Vol.12, Issue 10, page no.d766-d779, October-2025, Available :http://www.jetir.org/papers/JETIR2510398.pdf

"In Silico Elucidation of the Inhibitory Mechanism of Chickpea Peptide CaNCR63 against Staphylococcus aureus Sortase A", International Journal of Emerging Technologies and Innovative Research (www.jetir.org | UGC and issn Approved), ISSN:2349-5162, Vol.12, Issue 10, page no. ppd766-d779, October-2025, Available at : http://www.jetir.org/papers/JETIR2510398.pdf