Targeting Staphylococcal Cell–Wall Biosynthesis Protein FemX Through Steered Molecular Dynamics and Drug-Repurposing Approach

Staphylococcus
aureus-mediated infection
is a serious threat in this antimicrobial-resistant world. S. aureus has become a “superbug” by
challenging conventional as well as modern treatment strategies. Nowadays,
drug repurposing has become a new trend for the discovery of new drug
molecules. This study focuses on evaluating FDA-approved drugs that
can be repurposed against S. aureus infection. Steered molecular dynamics (SMD) has been performed for
Lumacaftor and Olaparib against staphylococcal FemX to understand
their binding to the active site. A time-dependent external force
or rupture force has been applied to the ligands to calculate the
force required to dislocate the ligand from the binding pocket. SMD
analysis indicates that Lumacaftor has a high affinity for the substrate
binding pocket in comparison to Olaparib. Umbrella sampling exhibits
that Lumacaftor possesses a higher free energy barrier to displace
it from the ligand-binding site. The bactericidal activity of Lumacaftor
and Olaparib has been tested, and it shows that Lumacaftor has moderate
activity along with biofilm inhibition potential (MIC value with conc.
128 μg/mL). Pharmacokinetic and toxicology evaluations indicate
that Lumacaftor has higher pharmacokinetic potential with lower toxicity.
This is the first experimental report where staphylococcal FemX has
been targeted for the discovery of new drugs. It is suggested that
Lumacaftor may be a potential lead molecule against S. aureus.