Chemistry Reference
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could be devoted to scaffold modifications to expand the candidate pool in lead
generation.
Since many druggable targets are promiscuous towards lipophilic ligands, it may
be interesting to modify the hydrophobic portions of hit compounds in scaffold
and analog design. Scaffold hopping is also defined as a computational technique
that identifies compounds containing a topogically different scaffold from the
parent compound with, however, improved or similar activity from a given
database. Very simple or complex compounds may require drastic changes,
i.e.
more scaffolds may be required to validate, synthesize or invalidate chemistry-
demanding efforts.
There is still a limited number of druggable targets. Their exploration is based on
known ligands or protein-ligand structures. Based on this knowledge, the question
then is how to design economically
viable drugs maintaining or improving
efficiency and pharmacokinetic (PK) profiles of existing therapies by designing
novel structural scaffolds.
Effectively, one of the strategies for discovering structurally novel compounds is
lead hopping (scaffold hopping), a relatively young concept applied from the
beginning of drug discovery. The method starts with known active compounds
yielding novel chemotypes by modifying the central core structure of the
molecules. Often modification of side chains is sufficient to overcome undesirable
properties associated with parent molecules. On the contrary it may be necessary
to modify the core structure of the scaffold.
The concept of scaffold hopping was introduced as a technique to identify
isofunctional molecular structures with significant different molecular backbones
emphasizing two key components. These are core structures and similar biological
activities of the new compounds relative to the parent compounds. Scaffold
hopping can also be classified into four groups,
i.e.
heterocycle replacements,
topology-based hopping, peptidomimetics and ring opening or closure.
Derivatives obtained from the parent compounds having novel core structures can
define scaffold hopping. However, how different should the derivative molecules
