Targeting Inhibitor of Enterococcus faecalis: Insights from Comparative Molecular Dynamics and Binding Free Energy Analyses

Abstract

For the past 50 years, antibiotics that target DNA gyrase have proven to be clinically successful. As a result, the search for novel gyrase inhibitors has intensified due to the rise in bacterial resistance. Since it is absent in eukaryotes yet essential in all bacteria, anti-bacterials target it aggressively. Although quinolones are a clinically approved medication, both Gram-positive and Gram-negative bacteria are developing resistance to them, which compromises their therapeutic efficacy. Thus, it is vital to identify novel compounds that can efficiently inhibit DNA gyrase. A recent experimental study shows that the R-enantiomer of compound 1 was likely to be a more favourable stereoisomer than the R-enantiomer in inhibiting the function of DNA gyrase. However, the molecular mechanisms of its selectivity and inhibition remain elusive. To gain insight into the observed inhibitory effect, molecular dynamics simulations have been employed to investigate the inhibitory mechanism as well as selectivity effect. MD simulation revealed that R-enantiomer selectively targeted the ATP-binding pocket residues, with the 2,4 di chloro carbazole ring’s group interacting into the small hydrophobic pocket provided by Asp 25, arg 26, Ile 182, Val 233, Arg 284, and Ala 286 in DNA gyrase. Finding the residues in the catalytic-binding site may pave the way for the development of a new structure-based inhibitor of highly selective DNA gyrase for the treatment of Enterococcus faecalis infection.