Molecular Interactions of Precocene Derivatives in Crystal Structures and in Silico Evaluation of Their Binding to Estrogen Receptors

Crystallographic studies of potential bioactive compounds provide insight into the mode of molecular recognition and the nature of intermolecular interactions responsible for receptor-binding. Bischromans, which are dimers of precocenes, have structural similarity with 17β-estradiol and are promising estrogen receptor (ER) agonists or antagonists. In order to understand the intermolecular interactions of biscroman-like scaffolds responsible for molecular recognition and aggregation, we analysed the crystal structures of 10 precocene derivatives in detail. The structures of derivatives 1 and 2 are reported in this study, and are compared with eight other previously reported precocene derivatives (3-10). Compounds 1-4 are precocene dimers, while 5-10 are stilbenoid derivatives of precocene. Although a hydroxyl functional group is present in 6 compounds, intermolecular hydrogen bonds are observed in the molecular packing of three derivatives, viz, 2, 5, and 8. Aromatic ring interactions are found in 9 out of 10 crystal structures, marking them as a major contributor in facilitating molecular aggregation. Molecular docking analysis indicates that compounds 1-10 have moderate to high binding affinity with ERα and ERβ. Notably, all derivatives that bind at the ligand-binding pocket showed favorable centroid…centroid distances with Phe404 (ERα) and Phe356 (ERβ), mimicking the binding of 17β-estradiol to the ER proteins.