Small-molecule 11β-HSD1 inhibitors are investigated as a treatment for metabolic syndrome, as well as for type 2 diabetes. Several 11β-HSD1 inhibitors are in late preclinical or early clinical development as the next generation of drugs in metabolic syndrome.

 

OTAVAchemicals 11β-HSD1 Targeted Library (860 compounds) has been designed with flexible molecular docking. For the docking, we used crystal structure of human 11β-HSD1 in complex with inhibitor and cofactor NADP (4C7K). The 11β-HSD1 binding pocket in the crystal structure includes bound cofactor which has been preserved during the docking. The most important polar interactions between the cocrystalized ligand and 11β-HSD1 in 4C7K include contacts with Ala172, Ser170 and Tyr183 residues. Presence of hydrogen bonds between docked ligands and these residues has been used as a selection criteria to retain the most promising compounds only. To filter molecular complexes obtained with the docking, a scoring cutoffs based on different scoring functions were used. Finally, the complexes selected with the H-bond and score filtering were subjected to visual analysis in order to discard ligands with improper binding mode.