TY - JOUR ID - 10442/17903 A1 - A1 - Kyriakis, E. A1 - A1 - Karra, A. G. A1 - A1 - Papaioannou, O. A1 - A1 - Solovou, T. A1 - A1 - Skamnaki, V. T. A1 - A1 - Liggri, P. G. V. A1 - A1 - Zographos, S. E. A1 - A1 - Szennyes, E. A1 - A1 - Bokor, É. A1 - A1 - Kun, S. A1 - et al. Y1 - 2020/// T1 - The architecture of hydrogen and sulfur σ-hole interactions explain differences in the inhibitory potency of C-β-d-glucopyranosyl thiazoles, imidazoles and an N-β-d glucopyranosyl tetrazole for human liver glycogen phosphorylase and offer new insights to structure-based design JF - Bioorganic & medicinal chemistry VL - 28 IS - 1 SN - 09680896 U3 - 10.1016/j.bmc.2019.115196 PB - Elsevier SP - 115196EP - UR - https://hdl.handle.net/10442/17903 N2 - C-Glucopyranosyl imidazoles, thiazoles, and an N-glucopyranosyl tetrazole were assessed in vitro and ex vivo for their inhibitory efficiency against isoforms of glycogen phosphorylase (GP; a validated pharmacological target for the development of anti-hyperglycaemic agents). Imidazoles proved to be more potent inhibitors than the corresponding thiazoles or the tetrazole. The most potent derivative has a 2-naphthyl substituent, a Ki value of 3.2 µM for hepatic glycogen phosphorylase, displaying also 60% inhibition of GP activity in HepG2 cells, compared to control vehicle treated cells, at 100 μM. X-Ray crystallography studies of the protein - inhibitor complexes revealed the importance of the architecture of inhibitor associated hydrogen bonds or sulfur σ-hole bond interactions to Asn284 OD1, offering new insights to structure-based design efforts. Moreover, while the 2-glucopyranosyl-tetrazole seems to bind differently from the corresponding 1,2,3-triazole compound, the two inhibitors are equipotent. ER -