protein; however, they indirectly influence the activity by inducing
conformational changes within the protein structure.
Identifying these sites and evaluating their druggability is very
complicated. Current tools employ both geometrical-based and
energy-based approaches to identify a binding site and assess its
druggability. While these methods can easily study catalytic sites,
they can poorly identify and study more complicated sites. This is
mainly due to the fact that they rely on a static structure of the
target protein, while an accurate prediction of these sites requires
the accommodation of protein flexibility during the binding site
search process. It also requires studying the structural dynamics of
the different hot spots for a protonated time scale.
In this context, molecular dynamics (MD) simulations became
an important tool in structure-based drug design to understand
backbone and side chain flexibilities for a given target. MD simula-
tions can be combined with current binding site identification tools
to study every single snapshot. This approach led to the successful
identification of novel sites in important targets.
This chapter focuses on overviewing the different methods
used to identify and evaluate binding sites within a given target. It
also highlights the importance of incorporating protein flexibility
within the search process and the use of MD simulation in this
process.5 Notes
- Traditional binding site identification methods can be classified
into either geometrical-based or energy-based methods. These
methods employ a static structure of the target protein and
identify hot spots on its surface. - Accounting for the protein flexibility can significantly improve
the binding site identification outcomes. Molecular dynamics
(MD) simulations is a reliable tool to explore the protein
dynamics and help identify cryptic sites that are now obviously
shown in a crystal structure. - Despite the great benefit of using MD simulations to accom-
modate for protein flexibility, MD simulations are limited. The
main limitation of MD is due to its reliance on a force field to
describe the atomic interactions within the simulated system.
This is a classical representation of the system, which only
allows the study of the atoms movements, without any refer-
ence to their electronic dynamics. Although this simplification
improves the computational speed for MD simulations and also
allows the expansion of its size, this approximation does not
allow the simulation of bond breakage and bond formation
reactions.
100 Tianhua Feng and Khaled Barakat