3.5 Docking studies
Docking studies were carried out to understand the possible binding
sites and thus the mechanism of action of Phormidin against bacterial
FAS II and human FAS I. Crystal structure of Bacillus subtilisFAS II with inhibitor Cerulenin bonded at beta-ketoacyl-ACP synthase II
domain and human FAS IKS-MAT di-domain were considered as a model for
the studies. Binding results were interpreted based on the scores
obtained in docking studies, as well as the theoretical binding energies
calculated from the docked poses. Possible amino acid residues involved
in binding and the type of interactions made by Phormidin with active
site residues are shown in Figure 4a. for FAS II and in Figure 4b. in
the case of FAS I. As seen from the Table 3, for both FAS II and FAS I,
the glide scores as well as the theoretically calculated binding
energies are better for Phormidin compared to that of both the other
inhibitors, Cerulenin and C75. Glide score is calculated based on
different parameters of ligand-protein interactions and it represents
the overall affinity of ligand-protein binding. MMGBSA simulates binding
free energy of ligand-protein interaction; more negative values
represent tighter binders. Parameters like number of H-bonds between
ligand atoms and active site residues, ligand interaction with number of
hydrophobic residues and the total number of van der Waals contacts
involved in ligand binding indicates the affinity and strength of ligand
enzyme interactions. Table 4 gives a comparison of total number of these
parameters with respect to Phormidin and other two FAS inhibitors in FAS
II and FAS I. It can be clearly seen that Phormidin has stronger
interaction with both FAS II and FAS I enzymes when compared to the
other known inhibitors. Also, the results of ADME prediction have been
summarized in Table 5.