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Evaluation of molecular model-based discovery of ecto-5’-nucleotidase inhibitors on the basis of X-ray structures
Journal of Cheminformatics volume 6, Article number: P13 (2014)
Ecto-5’-nucleotidase (e5NT) belongs to the family of metallophosphoesterases, hydrolyses AMP to adenosine, and is a regulator of the adenosine signaling pathway . It has been shown, that free adenosine is involved in various diseases and cancer progression [2, 3]. In a previous study, a molecular model of e5NT has been created and used for the identification of new sulfonamide inhibitors . Recently, X-ray structures of human e5NT in complex with different inhibitors were published . This made it possible to reevaluate the model building and virtual screening efforts in detail. An extensive analysis of the comparative e5NT model, built using a bacterial enzyme in the presence of 35% sequence identity as a template, showed that the model was topologically correct and had high accuracy within the active site region. Comparative docking studies were carried out to explore inhibitor binding characteristics within the X-ray structure and the model. The results provided plausible explanations for the successful identification of new e5NT inhibitors by model-based virtual screening and highlighted important parameters .
Zimmermann H, Zebisch M, Sträter N: Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signalling. 2012, 8: 437-502. 10.1007/s11302-012-9309-4.
Deaglio S, Robson SC: Ectonucleotidases as regulators of purinergic signalling in thrombosis, inflammation, and immunity. Adv Pharmacol. 2011, 61: 301-332.
Zhang B: CD73: a novel target for cancer immunotherapy. Cancer Res. 2010, 70: 6407-6411. 10.1158/0008-5472.CAN-10-1544.
Ripphausen P, Freundlieb M, Brunschweiger A, Zimmermann H, Müller CE, Bajorath J: Virtual screening identifies novel sulfonamide inhibitors of ecto-5‘-nucleotidase. J Med Chem. 2012, 55: 6576-6581. 10.1021/jm300658n.
Knapp K, Zebisch M, Pippel J, El-Tayeb A, Müller CE, Sträter N: Crystal structure of the human ecto-5’-nucleotidase (CD73): insights into the regulation of purinergic signaling. Structure. 2012, 20: 2161-2173. 10.1016/j.str.2012.10.001.
Furtmann N, Bajorath J: Evaluation of molecular model-based discovery of ecto-5’-nucleotidase inhibitors on the basis of X-ray structures. Bioorg Med Chem.
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Furtmann, N., Bajorath, J. Evaluation of molecular model-based discovery of ecto-5’-nucleotidase inhibitors on the basis of X-ray structures. J Cheminform 6, P13 (2014). https://doi.org/10.1186/1758-2946-6-S1-P13
- Virtual Screening
- Docking Study
- Site Region
- Binding Characteristic