7EZR

Indole-2-carboxylic acid derivatives as allosteric inhibitors of fructose-1,6-bisphosphatase

Summary for 7EZR

• Entry DOI: 10.2210/pdb7ezr/pdb
• Descriptor: Fructose-1,6-bisphosphatase 1, 5-ethyl-7-nitro-3-[3-oxidanylidene-3-(thiophen-2-ylsulfonylamino)propyl]-1H-indole-2-carboxylic acid, 1,6-di-O-phosphono-beta-D-fructofuranose (3 entities in total)
• Functional Keywords: fructose-1, 6-bisphosphatase, indole-2-carboxylic acids, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 150716.09

Authors

Wang, X.Y.,Zhou, J.,Xu, B.L. (deposition date: 2021-06-01, release date: 2022-06-01, Last modification date: 2023-11-29)

Primary citation

Wang, X.,Zhao, R.,Ji, W.,Zhou, J.,Liu, Q.,Zhao, L.,Shen, Z.,Liu, S.,Xu, B.
Discovery of Novel Indole Derivatives as Fructose-1,6-bisphosphatase Inhibitors and X-ray Cocrystal Structures Analysis.
Acs Med.Chem.Lett., 13:118-127, 2022

PubMed Abstract: Liver fructose-1,6-bisphosphatase (FBPase) is a key enzyme in the gluconeogenesis, and its inhibitors are expected to be novel antidiabetic agents. Herein, a series of new indole and benzofuran analogues were designed and synthesized to evaluate the inhibitory activity against FBPase. As a result, the novel FBPase inhibitors bearing -acylsulfonamide moiety on the 3-position of the indole-2-carboxylic acid scaffold (compounds and ) were identified with ICs at the submicromolar levels. Three X-ray crystal structures of the complexes were solved and revealed the structural basis for the inhibitory activity. The chemoinformatics analysis further disclosed the distinct binding features of this class of inhibitors, providing an insight for further modifications to create structurally distinct FBPase inhibitors with high potency and drug-like properties.

PubMed: 35059131
DOI: 10.1021/acsmedchemlett.1c00613

Experimental method

X-RAY DIFFRACTION (3.27 Å)