database selection, (3) molecular docking, and (4) analysis of
results. Careful analyses of the available information concerning
the structure and function of the investigated molecular
target along with its known ligands are highly recommended
when devising an SBVS workflow [25]. Once the molecular target
structure is selected, it undergoes important procedures aimed at
preparing it for molecular docking. Usually, these procedures con-
sist of adding hydrogen atoms (seeNote 1), eliminating noncrys-
tallographic water molecules, assigning partial charges and
specifying protonation states for the amino acid residues [26].
The next critical step is the selection of the set of compounds
that will be used in the molecular docking studies. Usually, freely
available virtual databases that encompass a wide chemical diversity
are used [27]. In general, these compound repositories are interac-
tive interfaces that allow for the application of chemical filters to
search and select focused subsets representing a specific chemical
space. Molecules in these databases are stored as line notations
(e.g., SMILES, SMARTS, or InChI files), which are automatically
converted into 3D structures with appropriate ionization states,
partial charges, and stereochemistry once downloaded [13, 27].
The next phase consists of docking the selected compounds
into the target binding site. The conformational search routine
probes the energy landscape of each compound, and those com-
pounds ranked as promising hits are selected for post-docking
analysis, the next stage of this process. This procedure involves
visualizing the predicted ligand–receptor complexes and enables
the examination of critical features, such as binding conforma-
tions and intermolecular interactions. The analysis of these ele-
ments is useful for deciding on which of the top-scoring
compounds have to be prioritized for experimental studies
[8, 10, 24]. Another important aspect that can be evaluated by
visualizing the structures is whether the docking solutions for
known ligands match crystallographic conformations. This step
is important for assessing whether the docking simulations can
reproduce experimental data.
Considering the above-discussed principles, it is clear that
outlining robust molecular docking and SBVS campaigns is not
a straightforward task. Given the success achieved by these
approaches and the variety of programs, algorithms, and resources
available, a wide diversity of strategies can be employed. Next, we
will provide a detailed workflow that will introduce to the reader
the basic tasks for conducting a molecular docking and SBVS
effort.
Molecular Docking and Structure-Based Virtual Screening 35