title: Computational analysis of human OGA structure in complex with PUGNAc and NAG-thiazoline derivatives.
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 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.
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, 66075-110, Belém, PA, Brazil.
authors.forename: Nelson Alberto N
authors.initials: NA
authors.lastname: de Alencar
authors.forename: Paulo Robson M
authors.initials: PR
authors.lastname: Sousa
authors.forename: José Rogério A
authors.initials: JR
authors.lastname: Silva
authors.forename: Jerônimo
authors.initials: J
authors.lastname: Lameira
authors.forename: Cláudio Nahum
authors.initials: CN
authors.lastname: Alves
authors.forename: Sergio
authors.initials: S
authors.lastname: Martí
authors.forename: Vicent
authors.initials: V
authors.lastname: Moliner
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001439:Bacteroides / Q000737:chemistry / Q000201:enzymology; D001665:Binding Sites; D003016:Clostridium perfringens / Q000737:chemistry / Q000201:enzymology; D018360:Crystallography, X-Ray; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D010091:Oximes / Q000737:chemistry*; D048448:Phenylcarbamates / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D040681:Structural Homology, Protein; D013816:Thermodynamics; D013844:Thiazoles / Q000737:chemistry*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; D007527:Isoenzymes; D008024:Ligands; D010091:Oximes; D048448:Phenylcarbamates; D013844:Thiazoles; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; C487818:N-acetylglucosamine thiazoline; D000117:Acetylglucosamine