Chemistry Reference
In-Depth Information
replacement of a substructure of a bioactive molecule with another substructure
that is similar in size and shape and also shares physicochemical properties,
having similar impact on molecular activity. Bioisosterism procedures try to
maintain the biological activity of the novel chemical entity and minimize bad
pharmaceutical properties related with the structure of the original query
molecule. The bioisosterism term is derived from the isosteres concept, which
defines group of molecules sharing the same number of atoms and valence
electrons, introduced in 1919 by the physicist Irving Langmuir [2]. A broader
definition of isosteres correlates molecules or substructures that have similar
physicochemical properties [3-5].
Bioiosterism is a molecular modification of Medicinal Chemistry strategy applied
during drug design projects when a lead compound is available [6]. The idea of
bioisosterism is centered on the usage of chemical diversity in order to optimize
pharmaceutical properties of lead compounds and generate active analogs,
replacing problematic substructures inside lead compounds by others presenting
similar physicochemical properties that can overwhelm the limitations observed
for the original bioactive molecules.
The main reasons that stimulate medicinal chemists to apply bioisosterism are to
optimize lead compounds, searching analogues with better selectivity, synthetic
accessibility, decreased toxicity, improved pharmacokinetics, enhanced solubility
and metabolic stability.
BIOSOSTERIC REPLACEMENTS
In practice, the most challenging task when performing bioiosteric replacements
during drug design projects is to select or identify the most relevant
interchangeable fragments in order to build novel analogues of a particular
interesting lead compound. The physical and chemical properties required in a
bioisosteric replacement procedure for a specific fragment in order to maintain the
biological activity of a lead compound depend on which extent these properties
contribute to activity and, of course, the global impact on molecular properties
generated by the influence of the molecular scaffold attached to the substituted
fragment [5]. Thus, suggesting appropriate bioisosteric replacements is a complex
