4MLH

Human Glucokinase in Complex with a Novel Amino Thiazole Allosteric Activator

Summary for 4MLH

• Entry DOI: 10.2210/pdb4mlh/pdb
• Related: 4MLE
• Descriptor: Glucokinase, alpha-D-glucopyranose, 3-(benzyloxy)-5-methyl-N-(4-methyl-1,3-thiazol-2-yl)pyridin-2-amine (3 entities in total)
• Functional Keywords: sugar kinase, allosteric activator, small molecule, transferase-transferase activator complex, transferase/transferase activator
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 51500.55

Authors

Voegtli, W.C. (deposition date: 2013-09-06, release date: 2013-09-25, Last modification date: 2024-02-28)

Primary citation

Hinklin, R.J.,Boyd, S.A.,Chicarelli, M.J.,Condroski, K.R.,Dewolf, W.E.,Lee, P.A.,Lee, W.,Singh, A.,Thomas, L.,Voegtli, W.C.,Williams, L.,Aicher, T.D.
Identification of a New Class of Glucokinase Activators through Structure-Based Design.
J.Med.Chem., 56:7669-7678, 2013

PubMed Abstract: Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, compounds that can activate GK may serve as effective treatments for type 2 diabetes. Herein we report the identification and initial optimization of a novel series of allosteric glucokinase activators (GKAs). We discovered an initial thiazolylamino pyridine-based hit that was optimized using a structure-based design strategy and identified 26 as an early lead. Compound 26 demonstrated a good balance of in vitro potency and enzyme kinetic parameters and demonstrated blood glucose reductions in oral glucose tolerance tests in both C57BL/6J mice and high-fat fed Zucker diabetic fatty rats.

PubMed: 24015910
DOI: 10.1021/jm401116k

Experimental method

X-RAY DIFFRACTION (2.9 Å)