4L3Q

Crystal structure of glucokinase-activator complex

Summary for 4L3Q

• Entry DOI: 10.2210/pdb4l3q/pdb
• Related: 4DHY
• Descriptor: Glucokinase, alpha-D-glucopyranose, 6-{3-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenyl}pyridin-2(1H)-one, ... (4 entities in total)
• Functional Keywords: glycolysis, diabetes, transferase-transferase activator complex, transferase/transferase activator
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 51626.67

Authors

Gajiwala, K.S.,Filipski, K.J. (deposition date: 2013-06-06, release date: 2013-07-24, Last modification date: 2023-09-20)

Primary citation

Filipski, K.J.,Guzman-Perez, A.,Bian, J.,Perreault, C.,Aspnes, G.E.,Didiuk, M.T.,Dow, R.L.,Hank, R.F.,Jones, C.S.,Maguire, R.J.,Tu, M.,Zeng, D.,Liu, S.,Knafels, J.D.,Litchfield, J.,Atkinson, K.,Derksen, D.R.,Bourbonais, F.,Gajiwala, K.S.,Hickey, M.,Johnson, T.O.,Humphries, P.S.,Pfefferkorn, J.A.
Pyrimidone-based series of glucokinase activators with alternative donor-acceptor motif.
Bioorg.Med.Chem.Lett., 23:4571-4578, 2013

PubMed Abstract: Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.

PubMed: 23831135
DOI: 10.1016/j.bmcl.2013.06.036

Experimental method

X-RAY DIFFRACTION (2.7 Å)