Computational Analysis of Human OGA Structure in Complex with PUGNAc and NAG-Thiazoline Derivatives
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Other documents of the author: De Alencar, Nelson Alberto N.; Sousa, Paulo Robson M.; Silva, José Rogério A.; Lameira, Jerônimo; Nahum Alves, Cláudio; Martí Forés, Sergio; Moliner, Vicent
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comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
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http://dx.doi.org/10.1021/ci2006005 |
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Title
Computational Analysis of Human OGA Structure in Complex with PUGNAc and NAG-Thiazoline DerivativesAuthor (s)
Date
2012Publisher
American Chemical SocietyISSN
1549-9596Bibliographic citation
Journal of Chemical Information and Modeling, 52, 10, p. 2775-2783Type
info:eu-repo/semantics/articlePublisher version
http://pubs.acs.org/doi/abs/10.1021/ci2006005Version
info:eu-repo/semantics/publishedVersionSubject
Abstract
The substitution of serine and threonine residues in nucleocytoplasmic proteins with 2-acetamido-2-deoxy-β-d-glucopyranose (O-GlcNAc) residues is an essential post-translational modification found in many multicellular ... [+]
The substitution of serine and threonine residues in nucleocytoplasmic proteins with 2-acetamido-2-deoxy-β-d-glucopyranose (O-GlcNAc) residues is an essential post-translational modification found in many multicellular eukaryotes. O-glycoprotein 2-acetamino-2-deoxy-β-d-glucopyranosidase (O-GlcNAcase) hydrolyzes O-GlcNAc residues from post-translationally modified serine/threonine residues of nucleocytoplasmic protein. O-GlcNAc has been implicated in several disease states such as cancer, Alzheimer’s disease, and type II diabetes. For this paper, a model of the human O-GlcNAcase (hOGA) enzyme based on the X-ray structures of bacterial Clostridium perfringens (CpNagJ) and Bacteroides thetaiotaomicrometer (BtOGA) homologues has been generated through molecular homology modeling. In addition, molecular docking, molecular dynamics (MD) simulations, and Linear Interaction Energy (LIE) were employed to determine the bind for derivatives of two potent inhibitors: O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) and 1,2-dideoxy-2′-methyl-R-d-glucopyranoso-[2,1-d]-Δ2′-thiazoline (NAG-thiazoline), with hOGA. The results show that the binding free energy calculations using the Linear Interaction Energy (LIE) are correlated with inhibition constant values. Therefore, the model of the human O-GlcNAcase (hOGA) obtained here may be used as a target for rational design of new inhibitors. [-]
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