Docking studies and molecular dynamics simulations of the binding characteristics of waldiomycin and its methyl ester analog to Staphylococcus aureus histidine kinase

Bacterial histidine kinases (HKs) are considered attractive drug targets because of their ability to govern adaptive responses coupled with their ubiquity. There are several classes of
HK inhibitors; however, they suffer from drug resistance, poor bioavailability, and a lack of
selectivity. The 3D structure of Staphylococcus aureus HK was not isolated in high-resolution coordinates, precluding further disclosure of structure-dependent binding to the specific
antibiotics. To elucidate structure-dependent binding, the 3D structure of the catalytic
domain WalK of S. aureus HK was constructed using homology modeling to investigate the
WalK–ligand binding mechanisms through molecular docking studies and molecular dynamics simulations. The binding free energies of the waldiomycin and its methyl ester analog
were calculated using molecular mechanics/generalized born surface area scoring. The key
residues for protein–ligand binding were postulated. The structural divergence responsible
for the 7.4-fold higher potency of waldiomycin than that of its ester analog was clearly
observed. The optimized 3D macromolecule–ligand binding modes shed light on the S.
aureus HK/WalK–ligand interactions that afford a means to assess binding affinity to design
new HK/WalK inhibitors.