physicochemical profile of each molecule. SBDD does not consider
pharmacokinetics aspects; therefore, estimation of properties such
as the partition coefficient (logP) and polar surface area (PSA) can
be used as a preliminary filter to remove compounds that are likely
to show permeability and solubility problems and, consequently,
poor pharmacokinetic profiles. Several computational tools are
freely available and should be used to estimate the physicochemical
properties of dataset molecules before performing an SBVS study
[48–50].
Another important aspect that should be considered is the
presence of crystallographic water molecules in the target binding
site. In some cases, these molecules are tightly bound to the molec-
ular target, requiring for their displacement the formation of at
least equally favorable ligand–receptor interactions. However, their
displacement is not required, as they can mediate specific ligand–re-
ceptor interactions, becoming a component of the binding site
themselves, which is the case for PI3Kδ. For crystallographic struc-
tures with high resolution, an interesting strategy is to perform
docking studies considering both situations—with and without
crystallographic water molecules. It should be noted that multiple
water molecules in the binding site can substantially increase the
complexity of the SBVS workflow since different combinations of
these molecules can be considered [51, 52].6 Notes
- In the protocol described in this chapter, the final structures
generated by the molecular docking program present implicit
non-polar hydrogen atoms. This result does not affect the
overall interpretation of the molecular interactions; however,
it is useful to recover all-atom 3D structures for use as inputs in
further computational studies (e.g., molecular dynamics simu-
lations). Full 3D structures in PDB format can be generated
from the final docking solutions by typing the following com-
mand in Open Babel:
obabel -ipdbqt molecule.pdbqt -h -opdb -O molecule.pdb- The software applications described in this workflow are all
free-of-charge and present detailed documentation on their
installation and use. Most of these applications are accessible
through package repositories for widely used UNIX-based
distributions and can be installed by typing a single command
in the terminal window. This is the case for BKChem, Open-
Babel, and AutoDock Vina. To verify the availability of the
Open Babel program in a Debian-based OS (e.g., Ubuntu),
enter the following command in the terminal:
Molecular Docking and Structure-Based Virtual Screening 47