Isostere

Isostere refers to atoms, ions, or molecules with similar shapes or volumes that can exhibit similar physical or chemical properties. The concept of isosterism is widely applied in medicinal chemistry, pharmaceutical sciences, and drug design to modify the structure of molecules to enhance efficacy, reduce toxicity, or modify the pharmacokinetic properties of a drug. Isosteres are used in the design of new drugs by replacing a functional group in a molecule with another that is physically or chemically similar.

History

The concept of isosterism was first introduced by Irving Langmuir in 1919. Langmuir used the term to describe atoms that have the same number of outer shell electrons. Over time, the definition has expanded to include molecules or ions that have similar shapes, electronic properties, or volumes, leading to similar biological activities.

Types of Isosteres

Isosteres can be classified into several types based on their nature and the extent of similarity:

Classical Isosteres

Classical isosteres include monoatomic or polyatomic ions or groups that have the same number of electrons and a similar size. Examples include the hydrogen atom (H) and the fluorine atom (F), or the hydroxyl group (OH) and the amino group (NH2).

Non-Classical Isosteres

Non-classical isosteres may not have the same number of electrons or exact size match but can still mimic the physical or chemical properties of the original molecule. These include bioisosteres like the tetrazole ring, which can mimic the carboxylate group.

Bioisosteres

Bioisosteres are a subset of non-classical isosteres specifically used in drug design. They are molecules or groups that can replace each other to modify the biological activity of a compound. Bioisosteres are used to increase potency, improve selectivity, or reduce toxicity of a drug.

Applications in Drug Design

The application of isosterism in drug design is a critical strategy for the development of new therapeutic agents. By replacing parts of a molecule with an isostere, researchers can:

• Enhance the drug's ability to bind to its target, increasing efficacy.
• Reduce undesirable side effects by modifying the drug's interaction with off-target proteins.
• Improve the pharmacokinetic properties, such as solubility and stability, of the drug.

Examples

One of the classic examples of isosterism in drug design is the replacement of a phenyl ring with a thiophene ring. This modification has been used in various drugs to improve their pharmacological properties. Another example is the substitution of a ketone oxygen with a sulfur atom to create a thioester, which can alter the drug's metabolism and increase its half-life.

Challenges

While isosterism provides a powerful tool in drug design, it also presents challenges. The introduction of an isostere can sometimes lead to unexpected changes in a drug's physical, chemical, or biological properties. Therefore, each modification must be carefully evaluated through computational modeling and empirical testing.