In silico Evaluation of Savirin Derivatives As Inhibitors of the agr Quorum Sensing System of Staphylococcus aureus

Abstract

Bacterial resistance to current antibacterial agents is a global challenge. The problem of bacterial resistance can be addressed by targeting the bacterial virulence gene expression, particularly quorum sensing (QS) mechanism which is cell to cell communication. Expression of various virulence genes is regulated by the agr QS system of S. aureus, which can be attenuated by inhibiting AgrA-DNA interactions. In this paper molecular docking study was done for savirin and its thirty derivatives with AgrA protein (PDB ID: 4G4K) of S. aureus in order to find out potential inhibitors of AgrA DNA binding activity. Out of the thirty derivatives of savirin, compounds 4, 7, 17, 20, 26 and 30 showed excellent binding scores (less than -10 kcal/mol). Molecular dynamics simulations of the above protein-ligand complexes along with savirin suggested that the complexes of compounds 4, 7, 17, 20, 26 and 30 are stable. MM/PB(GB)SA binding energy calculation showed that compounds 20 and 30 have higher binding affinity among the other compounds. Density functional theory based electronic properties of the compounds were also calculated. Compounds 20 and 30 possess very good drug likeness properties and hence, can be used as potential inhibitors against agr QS system of S. aureus.

GRAPHICAL ABSTRACT

Keywords:

• Drug resistance
• quorum sensing
• AgrA protein
• LytTR domain
• molecular docking