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Macrocycles exhibit intrinsic flexibility and often display a \u201cchameleon\u2010like\u201d 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\u2010 and solution\u2010state structures of the macrocycle grazoprevir, determined using microcrystal electron diffraction (MicroED) and nuclear magnetic resonance (NMR) spectroscopy. A low\u2010energy core conformation was consistently identified throughout the conformational journey, from solid formulation to solvated states and upon complexation with the biological target, while the vinyl cyclopropyl sulfonamide side chain reoriented. The presence of a common core conformation (RMSD up to 0.273 \u00c5) suggests that grazoprevir adopts a partial pre\u2010organized state, optimizing its suitability for target binding. In apolar environment, mimicking the cell membrane, intramolecular hydrogen bonding promoted the formation of compact conformations with reduced radii of gyration and solvent accessible 3D polar surface area, likely facilitating cell permeability. This work presents a comprehensive conformational trajectory of a macrocyclic chameleon and provides potential insights into understanding and characterizing cell permeability and chameleonicity of similar bRo5 therapeutics.<\/jats:p>","DOI":"10.1002\/chem.202502256","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T14:05:36Z","timestamp":1766066736000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Conformational Trajectory of the Molecular Chameleon Grazoprevir From Formulation to Target\u2010Bound"],"prefix":"10.1002","volume":"32","author":[{"given":"Lianne H. 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