Chemistry Reference
In-Depth Information
around each of the molecules using ZAP toolkit, a solver of the Poisson-
Boltzmann equation [19]. López-Ramos & Perruccio [31] described the use of this
tool as a ligand-based and target-based virtual screening. In this study, both virtual
screening and scaffold hopping methods were evaluated. The protein chosen was
hidroxyphenilpyruvatedioxigenase (HPPD) which is involved in the tyrosine
degradation pathway and thus, HPPD is a target for the treatment of
hypertyrosinemia in humans. In plants, this is an important enzyme for
plastoquinone and tocopherol production. Inhibition of this enzyme causes a
bleaching, followed by necrosis and death of the plant. The HPPD inhibitors have
generated a considerable number of herbicides which are marketed stemming
from research carried out in the agrochemical industries. The ligand mesotrione
(Fig.
3
) is the main representative of such an herbicides chemical class. Although
the methods of virtual screening (lead finding and scaffold hopping) are mostly
associated with the pharmaceutical context, in the agrochemical area the
fundamental concept of this approach remains the same as in drug discovery.
O
O
NO
2
O
O
S
O
Figure 3:
Chemical structure of mesotrione.
Examples from literature have shown the importance of the scaffold hopping
approach and its successful application. In the discovery of novel cannabinoid 1
(CB
1
) receptor, Boström
et al
. [32] demonstrate the concept of scaffold hopping in
Rimonabant (Acomplia
TM
), a CB
1
receptor antagonist for the treatment of obesity.
In order to improve physicochemical and pharmacodynamics properties, a
scaffold hopping approach was applied for altering the central fragment, the
methylpyrazole, in Rimonabant. This work described the design of a new series of
5,6-diaryl-pyrazine-2-amide derivatives and many of these compounds showed
IC
50
values below 10 nM for the CB
1
receptor (Fig.
4
).
