Macrocycles offer the drug designer substantial new opportunities to find therapies for previously intractable targets (e.g. protein-protein interaction) and provide access to new types of drug modality (e.g. chem. inducers of dimerization or mol. glues). Macrocycles also present substantial challenges: their synthesis is often lengthy and difficult, and the software tools used by mol. designers have, almost entirely, been developed and validated using data on traditionally drug-like, non-macrocyclic mols., making the software's predictive power on macrocycles uncertain. Together these factors massively increase the risk of instantiating any macrocyclic design hypothesis. One of the best-known classes of mol. glues, immunophilin ligands such as FK-506 and rapamycin, have long been of interest to drug designers, but progress on new therapies based on immunophilin ligands has been hampered by the same difficulties presented by other macrocycles: the enormous difficulty of their synthesis and the lack of well-validated tools for their design. Here we present our progress toward, and validation of, a structure-based design workflow to decode the mol. language of conformational control in structurally complex macrocycles like rapamycin, and the synthetic biol. platform that enables the production of specific analogs of immunophilin ligands and other macrocyclic natural products.
