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The GlcNAcstatin is a potent inhibitor of O-glycoprotein 2-acetamino-2-deoxy-β-D-glucopyranosidase, which has been related with type II diabetes and neurodegenerative disorders. Herein, hybrid quantum mechanics/molecular mechanics, molecular dynamics simulations, and potential of mean force were employed to study the interactions established between GlcNAcstatin and a bacterial O-GlcNAcase enzyme from Clostridium perfringens. The results reveal that the imidazole nitrogen atom of GlcNAcstatin has shown a better interaction with the active site of Clostridium perfringens in its protonated form, which is compatible with a substrate-assisted reaction mechanism involving two conserved aspartate residues (297 and 298). Furthermore, the quantum mechanics/molecular mechanics-molecular dynamics simulations appointed a strong interaction between Asp401, Asp298, and Asp297 residues and the GlcNAcstatin inhibitor, which is in accordance with experimental data. Lastly, these results may contribute to understand the molecular mechanism of inhibition of Clostridium perfringens by GlcNAcstatin inhibitor and, consequently, this study might be useful to design new molecules with more interesting inhibitory activity.

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.

Dopamine quinone is substrate of the NRH: Quinone Reductase enzyme (QR2) in the retina. The capability of accumulates endogenous dopamine in a neural tissue explains the association of certain neuropsychiatric diseases with polymorphisms in the QR2 promoter that causes overexpression via loss of the capability to bind repressors. However, QR2 doubly reduce other small compounds present in neural and non-neural tissues, being its physiology tissue dependent. In this context, the function of the neurohormone melatonin and analogues in the active site of this multifunctional enzyme is discussed in this mini review.