E-mail addresses: (S. Mishra), (AK Das).

Staphylococcus aureus causes a wide range of common diseases in both community-acquired and hospital-acquired environments. The treatment becomes challenging due to the emergence of multi-drug resistant strains such as Methicillin-Resistant Staphylococcus aureus (MRSA). This study aims to find some drugs that can be used in repurposing. Virtual screening has been performed against S. aureus FemX using 1,918 FDA-approved drugs, which provides the top 10 drugs with good binding affinity. These drugs are re-docked to understand their interaction patterns with FemX. Docking study shows a high score for three drugs, Lumacaftor, Dihy-droergocornine and Olaparib, and they are selected for molecular dynamics and quantum mechanical analysis. Molecular dynamics calculation shows that drug-FemX forms a stable structure compared to apo-FemX. Besides, the free energy landscape reveals that drug-protein complexes possess a single global minimum indicating their thermodynamic stability. MM/GBSA calculations show that Lumacaftor, Dihydroergocornine and Olaparib have the binding free energy of-30.03,-19.22 and-16.54 kcal/mol, respectively. The analysis of the wavefunctions from quantum chemical calculations reveals the presence of non-covalent interactions between drug and re-ceptor, dominated by aromatic n-n interactions. The drug-receptor interaction energy estimated from quantum mechanical methods suggests an important role of dispersion interactions in stabilizing the drug molecules with FemX. The hierarchy of computational methods of increasing accuracy employed in this work finds Lumacaftor to be the most potent inhibitor against FemX.

Automated summary

This study uses virtual screening and molecular simulations to identify drugs with potential inhibitory effects on Staphylococcus aureus FemX. Lumacaftor is found to be the most effective inhibitor.