Aims:
Validating the docking procedure and maintaining the structural water molecules at HDAC8
catalytic site.
Background:
Molecular docking simulations play a significant role in Computer-Aided Drug Design, contributing
to the development of new molecules. To ensure the reliability of these simulations, a validation process
called "Re-docking" is employed, focusing on the binding mode of a ligand co-crystallized with the protein of
interest.
Objective:
In this study, several molecular docking studies were conducted using five X-ray structures of
HDAC8-ligand complexes from the PDB.
Method:
Ligands initially complexed with HDAC8 were removed and re-docked onto the free protein, revealing
a poor reproduction of the expected binding mode. In response to this, we observed that most HDAC8-ligand
complexes contained one to two water molecules in the catalytic site, which were crucial for maintaining the cocrystallized
ligand.
Result:
These water molecules enhance the binding mode of the co-crystallized ligand by stabilizing the proteinligand
complex through hydrogen bond interactions between ligand and water molecules. Notably, these interactions
are lost if water molecules are removed, as is often done in classical docking methodologies. Considering
this, molecular docking simulations were repeated, both with and without one or two conserved water molecules
near Zn+2 in the catalytic cavity. Simulations indicated that replicating the native binding pose of co-crystallized
ligands on free HDAC8 without these water molecules was challenging, showing greater coordinate displacements
(RMSD) compared to those including conserved water molecules from crystals.
Conclusion:
The study highlighted the importance of conserved water molecules within the active site, as their
presence significantly influenced the successful reproduction of the ligands' native binding modes. The results
suggest an optimal molecular docking procedure for validating methods suitable for filtering new HDAC8 inhibitors
for future experimental assays.
