Biology Reference
In-Depth Information
Molecular Modeling of VicK' Protein and Its Potential Inhibitors
In order to get insight into the mechanism of inhibition, further studies were carried
out to verify the interaction modes between six compounds and the modeled struc-
ture of VicK' protein. Autodock 3.05 software was used for the docking simulation.
The binding conformations of these inhibitors in the ATP-binding pocket of the VicK
HATPase_c domain were shown in Figure 8. Although these structures are diverse,
the binding models of six potential inhibitors are similar, especially in the inner part
of the conserved domain. The surface of the binding pocket (Figure 2C) is divided
into two parts, one is hydrophobic inner part composed of residues ILE146, ILE175,
LEU180, ILE182, PHE238, and the other is the outer hydrophilic part consisted of
residues ASN149, LYS152, TYR153, ARG196, ARG199. All six compounds bind in
the pocket with rigid aromatic ring parts inserting into the inner part. In the large and
flexible outer part, these compounds adopt different interactions. All of them have hy-
drogen bond acceptors in the binding outer part. They could form hydrogen networks
with the polar residues to stabilize the substrate interactions. Their binding models
resemble natural substrate ATP much.
Figure 8.
Three-dimensional structural binding modes of six potential inhibitors to VicK' protein
derived from the docking simulations. The loop covered on the pocket was shown in tube. Six
compounds were shown in stick with different colors. Their binding conformations showed similar
interaction modes in the inner pocket. The binding diversity was restrained by small space and
hydrophobic characteristic. By contrast, these structures bound in the outer pocket in various ways.
This image was generated using the PyMol program [http://www.pymol.org/].
DISCUSSION
In bacteria, HKs have fundamental roles in TCS signal transduction pathways. Thus
they are major targets for antibacterial drug development. High structural and se-
quence homology of this kinase gene family makes the HKs ideal targets for homol-
ogy modeling and structure based virtual screening. The SBVS is an approach based
