While traditional small molecules excel at targeting buried active sites, they often struggle with flatter protein surface interactions. Macrocyclic compounds offer a promising alternative, binding with better affinity and selectivity to address previously “undruggable” targets. However, their larger size and structural complexity present unique computational challenges. This article explores how advanced 3D modelling capabilities enable more accurate prediction of macrocyclic conformations, providing practical considerations for effectively working with these promising therapeutic agents.
Macrocycles are an exciting class of compounds to tackle previously undruggable targets. In this article, we’ll explore how advances in computational modelling of macrocycles are unlocking efficiency improvements in macrocycle drug discovery that were previously only available for small molecules.
Beyond the Traditional Small Molecule Therapeutic Space
For decades, Lipinski’s Rule of Five has provided guidelines for the characteristics of compounds that are more likely to yield oral bioavailability.1 These include a molecular weight threshold of 500 Da, which has somewhat limited the exploration of chemical space by disfavouring larger molecules.
While small molecules excel at binding to deep, well-defined pockets within proteins, they struggle with broader, flatter surfaces, such as those that characterise protein-protein interactions.2 These are attractive therapeutic targets as they are fundamental to cell signalling and signal transduction.
Macrocycles, which are defined by ring structures containing 12 or more heavy atoms, bridge the gap between small molecules and biologics. They can bind to flatter, surface-level protein surfaces with high specificity, and despite surpassing the 500 Da threshold, can achieve good oral bioavailability. As a result, the industry has seen greater interest and investment in macrocyclic drug discovery.
Early concerns about metabolic stability were addressed by demonstrating that the constrained, cyclic architecture provides sufficient protection against proteolytic degradation.3 Additionally, strategic incorporation of non-natural amino acids can further enhance stability whilst maintaining biological activity.
Recent macrocyclic peptides that have been approved by the FDA for therapeutic use include rezafugnin (Rezzayo®), which is used to treat candidemia and invasive candidiasis in adults, and Lurbinectedin (Zepzelca®), for the treatment of metastatic small cell lung cancer.4
