Chemistry Reference
In-Depth Information
discovering novel core structures often ignoring potential conflicts between side
chains and targets.
Scaffold hopping can be a useful tool for overcoming undesirable properties such
as toxicity and poor exposure. Future software developments in scaffold hoping is
needed to incorporate guiding elements for achieving acceptable pharmacological
properties such as better PK profiles, reduced toxicity and improved absorption.
This could enable a generalized scaffold-hopping approach, which maximizes the
chemical diversity maintaining or even improving the biological activity and
pharmacological profiles of the original drug [244-254].
PHARMACOPHORE MODELING
Pharmacophore modeling is a very useful medicinal chemistry tool for the design
of therapeutic agents (new chemical entities). The concept was first introduced in
the beginning of the last century. It was defined as a molecular framework that
carries 'phoros'. These are the essential features responsible for a drug's
biological activity (phorons). These concepts have evolved/matured to a better
comprehension of the properties of ligand structures/targets.
The modern concept defines pharmacophores as an ensemble of steric and
electronic features necessary to ensure optimal interactions with specific
biological structures and trigger/block their biological response [255]. They can
be important in the search for molecules on targets. When used as
in silico
filters,
they can reduce substantially the cost and number of compounds processed in
subsequent stages. One does this by focusing on local similarity, studying the
specific arrangements and molecular determinants necessary for biological
activity processes and providing explanations for the predicted activity of
molecules. In order words, pharmacophores reflects how medicinal chemists can
characterize the binding ability of molecular ligands to biological targets.
The initial application of the pharmacophore hypothesis were two dimensional.
Tools were used in order to identify privileged motifs associated with biological
activity; explore/understand structure-activity relationships and guide the
synthesis of new bioactive compounds. However, these pharmacophores, with
