Accurate de novo design of membrane-traversing macrocycles.

ABSTRACT: We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed 184 6-12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6-12 residue size range cross membranes with an apparent permeability greater than 1 × 10^-6 cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an

SUBMITTER: Bhardwaj G 

PROVIDER: S-EPMC9490236 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature