residue properties for PPIs, and used this information to guide their
search for binding sites in heterodimer complexes [30]. The 2P2I
database gathers geometry information of interfaces, which comes
from known druggable PPIs’ interfaces. They summarize several
different properties of these interfaces after compared with general
PPI interfaces. The druggable PPIs’ interfaces are smaller, more
hydrophobic, and composed by fewer pockets. Additionally, the
druggable PPIs interfaces have less salt bridges and charged resi-
dues, but more hydrogen bonds at the interface [30].2.1.2 Energy-Based
Methods
Energy-based methods employ molecular docking as the main tool
to identify and characterize the binding sites on proteins. These
methods dock multiple probes to potential pockets and calculate
their binding free energies. These predicted energies reflect the
strength of the interactions of these probes within the target
[31]. Fragment-based mapping algorithm (FTMAP) is a popular
energy-based method. FTMAP was a developed version of its pre-
decessor, computational solvent mapping (CS-map) [32].
FTMAP uses a diverse library of 16 small organic molecules as
probes to search the whole target protein surface for potential
binding sites [7, 33]. These small organic probes have differentFig. 2Geometric-based binding site identification mechanism. The approach
scans the grid points outside the protein for protein–solvent–protein and surfa-
ce–solvent–surface events. When the regions reach the threshold of require-
ment, they can be labeled as potential binding sites90 Tianhua Feng and Khaled Barakat