The Therapeutic Potential of Macrocycles in Drug Discovery
Structural and Conformational Properties: Macrocycles exhibit distinct physicochemical characteristics that differentiate them from conventional small molecules. Their cyclic architectures confer a degree of conformational rigidity while maintaining three-dimensional complexity. This combination enables well-defined interactions with biological targets. As a result, macrocycles often demonstrate high binding affinity and selectivity, making them well-suited for engaging specific disease-relevant proteins.
Targeting Challenging Biological Interfaces: Macrocycles have demonstrated the ability to modulate targets that are traditionally considered difficult to drug, including protein–protein interactions (PPIs). Their size and surface complementarity allow them to engage extended and relatively featureless binding interfaces. In addition, emerging evidence suggests that macrocycles can interact with other complex biomolecules, such as RNA. These properties have led to increased interest in their application across therapeutic areas including oncology and infectious disease.
Oral Bioavailability: Despite frequently residing beyond conventional rule-of-five (Ro5) chemical space, certain macrocycles exhibit measurable oral bioavailability. This is often attributed to their ability to adopt conformations that balance permeability and solubility. Their structural features may also contribute to reduced susceptibility to enzymatic degradation, supporting systemic exposure following oral administration.
Pharmacokinetic Properties: Macrocycles can display extended half-lives relative to smaller molecules, resulting in prolonged duration of action. This may enable less frequent dosing regimens, which can be advantageous in a clinical context.
Chemical Diversity and Optimisation Potential: Macrocycles encompass a broad and diverse chemical space. Advances in synthetic and library-generation approaches have enabled the creation of structurally diverse macrocyclic compounds. This facilitates systematic exploration of structure–activity relationships and supports the optimisation of pharmacological properties.
Selectivity and Target Engagement: The size and structural complexity of macrocycles enable multiple, specific interactions with biological targets. This can result in high levels of target selectivity and reduced off-target activity, which are important considerations for therapeutic safety and efficacy.
In summary, macrocycles represent a versatile and expanding modality in modern drug discovery. Their ability to address previously intractable targets, combined with favourable pharmacological properties, positions them as a promising platform for the development of next-generation therapeutics.
