Regulation of 11β-hydroxysteroid dehydrogenase isoforms: pharmacophore search and molecular design of prospective 11β-HSD1 inhibitors

Introduction: Osteoporosis is an important medical and social public health problem in an aging or elderly society, the issue of pharmacological correction of which remains unresolved to this day. Materials and Methods: A design of prospective 11β-HSD1 inhibitors was performed on the basis of the literature data. A virtual screening of the designed compounds was performed using pharmacophore searching (DataWarrior, Flexophore), pharmacophore alignment (PhESA), and molecular docking (Jamda). 2D protein-ligand interaction maps were generated using PoseEdit, and 3D visualizations were produced in VMD. The cytotoxicity of the compounds was assessed in HEK-293 cells across a concentration range of 8–1024 μM, with IC50 values calculated in RStudio. Results and Discussion: A comprehensive virtual screening of prospective 11β-HSD1 inhibitors was performed, incorporating pharmacophore searching, PhESA alignment, and molecular docking against the 11β-HSD1 complex (PDB: 4YYZ). Several compounds (TS-897, TS-883, TS-945, and others) demonstrated Jamda Score values comparable to or exceeding that of the native ligand, indicating strong predicted binding affinity. Additional candidates were identified based on high pharmacophore similarity (>0.95). Among the 14 proposed compounds, four (IV-81, IV-91, IV-158) exhibited no cytotoxicity in HEK-293 cells (IC50 > 1024 µM). These findings support the potential of the synthesized azoloazine derivatives as novel 11β-HSD1 inhibitors for further in vitro and in vivo studies in osteoporosis therapy. Conclusion: As a result of this work, original azoloazine derivatives have been developed for further biological testing aimed at regulating the activity of 11β-hydroxysteroid dehydrogenase isoforms (11β-HSDs) for pharmacological correction of bone remodeling and osteoreparation disorders.