6fxh | pdb_00006fxh

Human cytosolic 5'-nucleotidase II soaked with 10mM 3-Phenyl-N-(9H-purin-6-yl)benzamide

spinqualitylabelsall models 6fxh, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6fxh is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, MG, SO4 Related: 5cqz, 5cr7, 4h4b, 6fir, 6fis, 6fiu, 6fiw, 2j2c Activity: 5'-nucleotidase, with EC number 3.1.3.5 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [5NTC_HUMAN] Autosomal recessive spastic paraplegia type 45. The disease is caused by mutations affecting the gene represented in this entry. Function [5NTC_HUMAN] May have a critical role in the maintenance of a constant composition of intracellular purine/pyrimidine nucleotides in cooperation with other nucleotidases. Preferentially hydrolyzes inosine 5'-monophosphate (IMP) and other purine nucleotides. Publication Abstract from PubMed The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200muM and among them three derivatives (12, 13 and 18) exhibited Ki in the sub-millimolar range (0.84, 2.4 and 0.58mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described as an important parameter. Lead optimization and biological evaluation of fragment-based cN-II inhibitors.,Guillon R, Rahimova R, Preeti, Egron D, Rouanet S, Dumontet C, Aghajari N, Jordheim LP, Chaloin L, Peyrottes S Eur J Med Chem. 2019 Feb 14;168:28-44. doi: 10.1016/j.ejmech.2019.02.040. PMID:30798051 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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