How drug-like can cyclic peptides be? Flexiblity vs. rigidity in the uncharted chemical space above MW ~1000
Large, macrocyclic peptides can achieve surprisingly high membrane permeability, although the properties that govern permeability in this chemical space are only beginning to come into focus, and many questions remain. One notable feature of known, “rule-breaking” macrocycle drugs is that they tend to be molecular chameleons, adopting one conformation in water and a different, more lipophilic conformation as they pass through the cell membrane. How important is this “chameleonicity” in determining their overall drug-likeness? We recently stumbled upon a model system with a molecular weight of ~1000 Da, in which both rigid and chameleonic compounds showed high permeability over a wide lipophilicity range, with peak permeabilities differing significantly depending on scaffold rigidity. Our findings indicate that modulating lipophilicity can be used to engineer favorable drug-like properties into both rigid and flexible macrocyclic peptides, and that scaffold rigidity can be used to tune properties in this interesting chemical class.