5CR7

Human cytosolic 5'-nucleotidase II in complex with N-(9H-Purin-6-yl)-3-(3-pyrrol-1-ylphenyl)benzamide

Summary for 5CR7

• Entry DOI: 10.2210/pdb5cr7/pdb
• Related: 4H4B 5CQZ
• Descriptor: Cytosolic purine 5'-nucleotidase, ~{N}-(7~{H}-purin-6-yl)-3-(3-pyrrol-1-ylphenyl)benzamide, ACETATE ION, ... (7 entities in total)
• Functional Keywords: complex, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P49902
• Total number of polymer chains: 2
• Total formula weight: 130803.21

Authors

Aghajari, N.,Preeti, P. (deposition date: 2015-07-22, release date: 2016-01-13, Last modification date: 2024-01-10)

Primary citation

Marton, Z.,Guillon, R.,Krimm, I.,Rahimova, R.,Egron, D.,Jordheim, L.P.,Aghajari, N.,Dumontet, C.,Perigaud, C.,Lionne, C.,Peyrottes, S.,Chaloin, L.
Identification of Noncompetitive Inhibitors of Cytosolic 5'-Nucleotidase II Using a Fragment-Based Approach.
J.Med.Chem., 58:9680-9696, 2015

PubMed Abstract: We used a combined approach based on fragment-based drug design (FBDD) and in silico methods to design potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), which has been recognized as an important therapeutic target in hematological cancers. Two subgroups of small compounds (including adenine and biaryl moieties) were identified as cN-II binders and a fragment growing strategy guided by molecular docking was considered. Five compounds induced a strong inhibition of the 5'-nucleotidase activity in vitro, and the most potent ones were characterized as noncompetitive inhibitors. Biological evaluation in cancer cell lines showed synergic effect with selected anticancer drugs. Structural studies using X-ray crystallography lead to the identification of new binding sites for two derivatives and of a new crystal form showing important domain swapping. Altogether, the strategy developed herein allowed identifying new original noncompetitive inhibitors against cN-II that act in a synergistic manner with well-known antitumoral agents.

PubMed: 26599519
DOI: 10.1021/acs.jmedchem.5b01616

Experimental method

X-RAY DIFFRACTION (2.9 Å)