Computational Analysis of Human OGA Structure in Complex with PUGNAc and NAG-Thiazoline Derivatives

• Published in: Journal of chemical information and modeling 2012-10, Vol.52 (10), p.2775-2783
• Main Authors: Alencar, Nelson Alberto N. de, Sousa, Paulo Robson M, Silva, José Rogério A, Lameira, Jerônimo, Alves, Cláudio Nahum, Martí, Sergio, Moliner, Vicent
• Format: Article
• Language: English
• Subjects: Acetylglucosamine - analogs & derivatives; Acetylglucosamine - chemistry; Analytical chemistry; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacteroides - chemistry; Bacteroides - enzymology; beta-N-Acetylhexosaminidases - antagonists & inhibitors; beta-N-Acetylhexosaminidases - chemistry; Binding Sites; Biological and medical sciences; Clostridium perfringens - chemistry; Clostridium perfringens - enzymology; Crystallography, X-Ray; Disease; Eukaryotes; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - chemistry; Kinetics; Ligands; Medical sciences; Molecular Docking Simulation; Molecular structure; Molecules; Oximes - chemistry; Phenylcarbamates - chemistry; Protein Binding; Protein Conformation; Proteins; Structural Homology, Protein; Thermodynamics; Thiazoles - chemistry; Tumors
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci2006005

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.