Computational Drug Discovery and Design

shock protein 90 N-terminal domain (Hsp90) and the HIV-1

protease (HIVpr). MDmix method showed more accurate interac-

tion map and provided affordable water displaceability predictions

compared with normal energy-based methods, such as Grid

[27, 56].

2.8 WaterMap WaterMap is another MD-based approach for binding site identifi-
cation. The method employs explicit water as the only solvent
molecules interacting with the protein. WaterMap relies on the
tendency for druggable binding sites to have a higher density of
thermodynamic unstable hydration sites. Accordingly, the method
uses statistical analysis techniques to identify these locations within
a given target [60].

3 Cases Studies

Following the description of the different MD-based methods for

binding site identification, the next section will provide recent case

studies from the literature.

3.1 A Catalytic Site
Problem: Viral
Neuraminidase

As mentioned above, catalytic active sites are the primary type of

druggable targets in drug development and they always have signif-

icant geometric features over allosteric sites. Neuraminidase

enzymes represent an example of such targets and are usually

targeted as the antigenic determinants on the surface of the influ-

enza virus. Neuraminidase has one catalytic site that cleaves sialic

acid and promotes new virus particles release [61]. Oseltamivir and

zanamivir are both effective orthosteric inhibitors that bind to the

active site (Fig.6).

Neuraminidase exhibits a high degree of selectivity among

structurally similar compounds. The N1 subtype specifically binds

Fig. 62D chemical structure of oseltamivir (a) and zanamivir (b). They are both orthosteric inhibitors bind to
the active site of neuraminidase. Generated by Maestro

Prediction of Druggable Binding Sites 97