Dock Prep tool available in Chimera, which can be accessed by
selectingTools!Structure Editing!Dock Prep.Leaving enabled
all options except forDelete solvent, Delete non-complexes ionsand
Add chargesis the recommended setting. After choosing these
settings, a second window will allow the parameterization of the
protonation states. This option is useful when the system has
multiple protonation possibilities for the binding site residues. In
this case, we will keep the default protonation states. SelectOKon
the current window, and when the next option becomes available,
save the generated receptor structure in the working directory as
receptor.mol2.3.2.3 Running
the Molecular Docking
Simulation
Having prepared the ligand and receptor input files, we will dock
idelalisib into the binding cavity of PI3Kδ. Using Chimera, open
the 3D structure of idelalisib (ligand.pdb) and go toTools!
Surface/Binding Analysis!AutoDock Vina. A new window will
pop up with several options describing the parameters that will be
used for docking (Fig.2a). In theOutput filesection, enter a name
for the file that will record the final docking results (e.g.,run1)in
the previously createdDockingfolder, and click on Set Output
Location. In theReceptorandLigandoptions, choose the receptor
and ligand to be used (these are4XE0andligand.pdb, respectively).
Over the blank fields in theReceptor searcharea, enter the X, Y, Z
coordinates recorded in Subheading3.2.2 in theCenter item
(Fig.2a). The next field, namedSize, defines the length in A ̊ of
each side of the box that will delimitate the binding site. The
optimal value for this parameter changes according to the volume
and geometry of the binding site of the system under study. In
general, this parameter should include all residues that could
engage in intermolecular interactions with the ligand; however, it
should not be excessively large because that could cause staggering
of the conformational search. A reasonable value to be selected in
our case is 15 for all axes.
After filling the parameters for the binding site, a wire-frame
box showing the selected binding site region will appear (Fig.2a).
Next, we should consider the parameters for receptor and ligand
handling. First, the optionAdd hydrogens in Chimerashould be
ignored, as we already set up protonation states during receptor
preparation. Furthermore, because Autodock Vina considers
hydrogen atoms bound exclusively to polar atoms to compute the
molecular interactions, enableMerge charges and remove non-polar
atomsandMerge charges and remove lone pairsin both Receptor and
Ligand options. Because we do not have chains with non-standard
residues, settings toIgnore chains of non-standard residuesand
Ignore all non-standard residueshave no effect and should be
ignored. In addition, we should consider the presence of the twoMolecular Docking and Structure-Based Virtual Screening 41