Role of non-covalent interactions in the conformational stability of bicalutamide in different solvent environments: Insights from quantum-chemical calculations and NMR spectroscopy

статья
Авторы публикации: 
Mololina A. A. , Sobornova V. V. , Belov K. V. , Krestyaninov M.A. , Khodov I. A.
Журнал: 
Journal of Molecular Liquids
Год публикации: 
2025
Том/страницы: 
V. 423. – Art. 126921 .
This study explores the solvent-dependent conformational equilibrium of bicalutamide (BCL), an antiandrogenic drug, through quantum-chemical calculations and nuclear magnetic resonance (NMR) spectroscopy. The findings demonstrate that solvent environments strongly affect BCL’s conformational dynamics. In benzene (C6H6), the «open» conformation is predominantly stabilized, driven by the solvent’s localization between BCL’s cyclic fragments and inducing a maximum deformation energy. Conversely, acetonitrile (CH3CN), dimethyl sulfoxide (DMSO), and chloroform (CHCl3) favor the «closed» conformation, exhibiting lower deformation energies.
NOESY spectroscopy provided quantitative insights into the distribution of conformers across solvents, revealing a significant solvent-dependent trend. In C6D6, the «open» conformer accounted for 84.7% of the population, whereas in CD3CN, DMSO‑d6, and CDCl3, the «closed» conformer dominated, with proportions of 60.4%, 80.5%, and 94.8%, respectively. This trend correlates with solvent polarity, as indicated by acceptor number (AN) values: solvents with higher AN values (e.g., CDCl3 and DMSO‑d6) preferentially stabilize the «closed» conformer, while those with lower AN values (e.g., benzene) favor the «open» conformer.
The results underscore the critical role of non-covalent interactions in conformer stabilization, emphasizing their relevance in drug formulation and the selection of polymorphic forms. This study not only deepens understanding of BCL’s conformational behavior but also provides valuable guidance for the design and optimization of pharmaceutical compounds exhibiting conformational polymorphism.
Опубликовано:
Колкер Римма Семеновна
(14.05.2025)