Conformational Trajectory of the Molecular Chameleon Grazoprevir From Formulation to Target-Bound.

ABSTRACT: Macrocycles represent a promising class of beyond-rule-of-5 (bRo5) therapeutics, capable of targeting proteins traditionally considered undruggable by conventional small molecules. Macrocycles exhibit intrinsic flexibility and often display a "chameleon-like" ability to adapt to their environment, thereby enhancing their oral bioavailability. Describing their structures and conformational changes is essential for advancing their development in the bRo5 space. In this study, we present the novel solid- and solution-state structures of the macrocycle grazoprevir, determined using microcrystal electron diffraction (MicroED) and nuclear magnetic resonance (NMR) spectroscopy. A low-energy core conformation was consistently identified throughout the conformational journey, from solid formulation

SUBMITTER: Wieske LHE 

PROVIDER: S-EPMC12929930 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature