Chemistry Reference
In-Depth Information
assumes that the binding affinity can be extracted from simulations of the free and
bound states of the ligand whereas, however, two MD simulations are needed, one
for the complex and the other for free ligand in water. However, there is still
absence of proven accuracy for guide lead optimization [364, 365]. Some of these
topics will be discussed again in subsequent sections.
WATER AND SOLVATION EFFECTS
Water molecules and solvation effects are key components in influencing binding
site dynamics as well as protein-ligand recognition. This is however difficult even
at the quantum mechanical level, despite the chemical simplicity involved. It has
been assumed that a strong binder should displace the water molecules present
initially at the receptor surface and restored, subsequently to the bulk solvent.
However, water molecules with multiple hydrogen bonds could provide enthalpy
contributions out-weighing entropic cost of its immobilization [367-373].
Permanently bound waters can be identified whereas favorably bound receptor
waters are not considered as unmovable since a ligand may still displace them.
Bridging waters may be a by-product of crystalization conditions. Water
molecules can be trapped in an energetically unstable position if it locks a
favorable protein conformation.
Such waters that define highly druggable hot spots can be prioritized for
desolvation when designing potent binders. There may be predictive improvement
requiring however human expertise and intervention. Computational approaches
can assess the impact of water molecules on ligand binding.
Pharmaceutical and manufacturing drug development spend considerable time to
identify appropriate solvent to scale manufacturing. Desolvation penalty is
important in drug design. There is a variety of models (explicit and implicit) to
describe biomolecules in solution. When the problem is treated explicitly,
electrostatic problems are investigated by averaging over a large number of
systems configurations. In addition to two hydrogens and oxygen, the waters can
also have zero mass charges to incorporate polarizability. Early models were used
to reproduce quantitatively the properties of water. Some of these models use a
