Identification of natural compounds as inhibitors of Clumping Factor A in Staphylococcus aureus to combat bovine mastitis: An in-Silico approach

Abstract

Bovine mastitis is a significant and economically impactful disease affecting dairy cattle globally, leading to decreased milk production, higher treatment costs, compromised genetic potential, animal mortality, and substantial economic losses. Mastitis is a major bovine disease caused by various organisms, with Staphylococcus aureus being one of the most virulent and prevalent pathogens responsible for bovine mastitis. The overuse of antibiotics has led to antimicrobial resistance and potential adverse effects on human health, necessitating the exploration of novel antibacterial therapeutics. This study employed computational methodologies, including structure-based virtual screening, molecular docking, ADMET prediction, and molecular dynamics (MD) simulations, to identify potential ClfA inhibitors of Staphylococcus aureus. A library of fifty-two natural compounds was screened, all exhibiting promising binding affinities (≤−8.0 kcal/mol). The top ten compounds underwent ADMET predictions, with seven satisfying Lipinski's rule of five and displaying pharmacokinetic properties. Further analysis using MD simulations was conducted on three compounds - Diaporthalasin, Oridonin, and Salvianolic acid A. Notably, Oridonin and Salvianolic acid exhibited strong stability in MD simulations, with RMSD values below 2.5 Å and consistent hydrogen bonding interactions with ClfA. Additionally, binding free energy calculations using MM-PBSA/MM-GBSA confirmed favorable interactions, with Oridonin exhibiting binding free energy of −30.4 kcal/mol and Salvianolic acid A at −28.7 kcal/mol. These findings suggest that Oridonin and Salvianolic Acid A can be considered for preclinical trials as potential candidates for veterinary drugs targeting mastitis caused by S. aureus.