Over the past two decades, advances in SBDD have been
fostered by the integration of spectroscopic methods, such as
X-ray crystallography, and in silico techniques, such as molecular
dynamics, homology modeling and molecular docking [4]. The
synergistic use of these methodologies, particularly in the preclini-
cal phase of the R&D process, has enabled the determination of the
3D structures of many biological macromolecules along with the
accurate characterization of their binding site features, such as steric
and electrostatic properties. This valuable knowledge has been the
key to the understanding of ligand–receptor molecular recognition
phenomena [5]. By integrating these data with up-to-date technol-
ogies in pharmaceutical R&D, SBDD has successfully supported
the development of pioneering therapies for highly complex and
prevalent conditions [6].
The use of SBDD strategies enables the conception of ligands
with specific steric and electrostatic properties that will effectively
interact with a target pharmacological receptor [4, 5]. SBDD con-
sists of a cyclic process that begins with the resolution of the 3D
structure of the molecular target. Next, molecular modeling inves-
tigations are performed to find putative ligands. Subsequently,
promising compounds are commercially purchased or synthesized,
followed by experimental evaluation of potency, affinity, and selec-
tivity against the investigated receptor. Once active molecules are
identified, the 3D structure of the ligand–receptor complex is
determined, enabling the identification of the intermolecular inter-
actions that drive the molecular recognition process. Additionally,
determining the structure of the ligand–receptor complex enables
the construction of relationships between biological activity and
structural features [7]. Finally, taking into account these studies,
molecular optimization efforts are conducted to improve the ligand
properties, mainly those related to affinity, selectivity, and efficiency.1.1 Molecular
Docking
Molecular docking is a broadly used SBDD technique. This tech-
nique is applied to predict the most likely 3D conformations of
small-molecule ligands within target binding sites and to provide
quantitative projections of the energy variations involved in the
intermolecular recognition event [8]. In addition, these quantita-
tive estimations of the binding energetics provide rankings for the
docked compounds, which is a useful parameter for selecting
ligands for experimental profiling. Molecular docking can be
divided into two distinct steps: exploration of the ligand conforma-
tional space within the binding cavity and estimation of the binding
energy for each predicted conformation [9, 10].1.1.1 Conformational
Search
To explore the conformational space, molecular docking programs
modify the structural parameters of the ligands, such as dihedral
angles and translational and rotational degrees of freedom. Two
strategies are usually employed by conformational search32 Ricardo N. dos Santos et al.