Classical bioisosteres Classical bioisosterism was originally formulated by James Moir and refined by
Irving Langmuir as a response to the observation that different atoms with the same
valence electron structure had similar biological properties. For example, the replacement of a
hydrogen atom with a
fluorine atom at a site of
metabolic oxidation in a drug candidate may prevent such metabolism from taking place. Because the fluorine atom is similar in size to the hydrogen atom the overall topology of the molecule is not significantly affected, leaving the desired biological activity unaffected. However, with a blocked pathway for metabolism, the drug candidate may have a longer half-life. •
Procainamide, an
amide, has a longer duration of action than
Procaine, an
ester, because of the isosteric replacement of the ester
oxygen with a
nitrogen atom. Procainamide is a classical bioisostere because the valence electron structure of a disubstituted oxygen atom is the same as a trisubstituted nitrogen atom, as Langmuir showed. Another example is seen in a series of anti-bacterial
chalcones. By modifying certain substituents, the pharmacological activity of the chalcone and its toxicity are also modified.
Non-classical bioisosteres Non-classical bioisosteres may differ in a multitude of ways from classical bioisosteres, but retain the focus on providing similar sterics and electronic profile to the original functional group. Whereas classical bioisosteres commonly conserve much of the same structural properties, nonclassical bioisosteres are much more dependent on the specific binding needs of the ligand in question and may substitute a linear functional group for a cyclic moiety, an alkyl group for a complex heteroatom moiety, or other changes that go far beyond a simple atom-for-atom switch. For example, a chloride -Cl group may often be replaced by a trifluoromethyl -CF3 group or by a cyano -C≡N group. Depending on the particular molecule used, the substitution may result in little change in activity, or either increased or decreased affinity or efficacy - depending on what factors are important for ligand binding to the target protein. Another example is aromatic rings, where a
phenyl -C6H5 ring can often be replaced by a different aromatic ring such as
thiophene or
naphthalene which may improve efficacy, change specificity of binding or reduce metabolically labile sites on the molecule, resulting in better pharmacokinetic properties. •
Alloxanthine is an inhibitor of
xanthine oxidase. It is also an isostere of
xanthine, the normal substrate for the
enzyme. Alloxanthine is considered a non-classical bioisostere because of the scaffold change. : •
Silafluofen is an
organosilicon analogue of
pyrethroid insecticide Etofenprox, wherein a carbon center has been replaced by isosteric silicon, and in addition, one hydrogen atom is replaced by isosteric fluorine atom. ==Other applications==