6E0E

Crystal structure of Glucokinase in complex with compound 6

Summary for 6E0E

• Entry DOI: 10.2210/pdb6e0e/pdb
• Descriptor: Glucokinase, alpha-D-glucopyranose, 2-({2-[(4-methyl-1,3-thiazol-2-yl)amino]pyridin-3-yl}oxy)benzonitrile, ... (4 entities in total)
• Functional Keywords: glucokinase, glucokinase activator, structure-aided design, structure-based design, type ii diabetes, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 50752.55

Authors

Hinklin, R.J.,Baer, B.R.,Boyd, S.A.,Chicarelli, M.D.,Condroski, K.R.,DeWolf, W.E.,Fischer, J.,Frank, M.,Hingorani, G.P.,Lee, P.A.,Neitzel, N.A.,Pratt, S.A.,Singh, A.,Sullivan, F.X.,Turner, T.,Voegtli, W.C.,Wallace, E.M.,Williams, L.,Aicher, T.D. (deposition date: 2018-07-06, release date: 2019-07-10, Last modification date: 2024-03-13)

Primary citation

Hinklin, R.J.,Baer, B.R.,Boyd, S.A.,Chicarelli, M.D.,Condroski, K.R.,DeWolf Jr., W.E.,Fischer, J.,Frank, M.,Hingorani, G.P.,Lee, P.A.,Neitzel, N.A.,Pratt, S.A.,Singh, A.,Sullivan, F.X.,Turner, T.,Voegtli, W.C.,Wallace, E.M.,Williams, L.,Aicher, T.D.
Discovery and preclinical development of AR453588 as an anti-diabetic glucokinase activator.
Bioorg.Med.Chem., 28:115232-115232, 2020

PubMed Abstract: Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can activate GK could provide a therapeutic benefit. Herein we report the further structure activity studies of a novel series of glucokinase activators (GKA). These studies led to the identification of pyridine 72 as a potent GKA that lowered post-prandial glucose in normal C57BL/6J mice, and after 14d dosing in ob/ob mice.

PubMed: 31818630
DOI: 10.1016/j.bmc.2019.115232

Experimental method

X-RAY DIFFRACTION (2.7 Å)