A Quantum Mechanics/Molecular Mechanics Study of the Protein−Ligand Interaction of Two Potent Inhibitors of Human <i>O</i>-GlcNAcase: PUGNAc and NAG-Thiazoline

Lameira, Jerônimo; Alves, Cláudio Nahum; Moliner, Vicent; Martí, Sérgio; Kanaan, Natalia; Tuñón, Iñaki

doi:10.1021/jp804626j

Cited by 27 publications

(26 citation statements)

References 32 publications

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“…Since O-GlcNAcylation is regulated by O-GlcNAcase, the modulation of O-GlcNAc levels with small molecule inhibitors of this enzyme should be a suitable strategy for detecting the functions of O-GlcNAcylation in a range of cellular processes. While experimental [21][22][23][24] and theoretical [25][26][27] investigation about the design, synthesis, and characterization of these kinds of molecules have been done, detailed studies of these molecules are desirable.…”

Section: Enzymatic Molecular Mechanism Of the Human O-glcnacase 21mentioning

confidence: 99%

Enzymatic Molecular Mechanism of the Human O-GlcNAcase to Design New Inhibitors: A Quantum Mechanical Approach

Ghiasi

Hasanzade

2014

Journal of Carbohydrate Chemistry

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In this study the catalytic mechanism of O-glycoprotein 2-acetamino-2-deoxy-β-Dglucopyranosidase (O-GlcNAcase) has been studied by using density functional theory (DFT) at the B3LYP level and split-valance 6-311G * * basis set. The results indicate that the reaction path takes place in a two-step mechanism. In the first step, Asp 174 polarizes the 2-acetamido group, which makes it act as a catalytic nucleophile to form the oxazoline intermediate. In the following step, Asp 175 acts as a general base to promote the attack of one water molecule at the anomeric center to produce the β-hemiacetal product. This reaction path involves two transition states (Ts1 and Ts2) and one intermediate.

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Section: Enzymatic Molecular Mechanism Of the Human O-glcnacase 21mentioning

confidence: 99%

Enzymatic Molecular Mechanism of the Human O-GlcNAcase to Design New Inhibitors: A Quantum Mechanical Approach

Ghiasi

Hasanzade

2014

Journal of Carbohydrate Chemistry

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“…Cutoffs for the nonbonding interactions were applied by a switching scheme, within a 14 to 16 Å radius range. As the system was prebalanced, 2000 ps of QM/MM molecular dynamics was performed for each of the two systems, with steps of 0.001 ps [44,53,54].…”

Section: Molecular Dynamicsmentioning

confidence: 99%

Virtual Screening and Molecular Dynamics Simulations from a Bank of Molecules of the Amazon Region Against Functional NS3-4A Protease-Helicase Enzyme of Hepatitis C Virus

Pinheiro

Duarte

Alves

et al. 2015

Appl Biochem Biotechnol

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Hepatitis C virus (HCV) infection is a disease that affects approximately 3% of the global population and requires new therapeutic agents without the inconvenience associated with current anti-HCV treatment. This paper reports on a study of a virtual screening and a molecular dynamics simulation of compounds derived from natural products from the Amazon region that are potentially effective against the NS3-4A enzyme of HCV, which plays an important role in the replication process of this virus. According to the results of the molecular docking calculations and subsequent consensual analysis, the best scored compounds showed interactions between hydrogen and residues of the catalytic triad as well as interactions with residues that guide ligands to the active site of the enzyme. They also showed stability in the molecular dynamics simulation, as the structures preserved important interactions at the active site of the enzyme. The root mean square deviation (RMSD) values were stabilized at the end of the simulation time. Such compounds are considered promising as novel therapies against HCV.

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“…The computational procedures based on QM/MM (see also the review article by J. Gascon in this issue) combine the strengths of both QM (accuracy) and molecular mechanics (MM) (efficiency) methods, and are widely employed to model chemical reactions and other electronic processes in biomolecular systems [26][27][28][29][30][31][32][33][34][35][36]. QM/MM can be used for preparing the structures of small molecules and proteins, such as optimizing the binding poses obtained from docking [37], and refining the geometries of enzyme active sites obtained from a harmonically restrained minimization with MM [38], or X-ray structures [39].…”

Section: Qm/mmmentioning

confidence: 99%

Quantum Mechanical Methods for Drug Design

Zhou

Huang

Caflisch

2010

CTMC

111

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Quantum mechanical (QM) methods are becoming popular in computational drug design and development mainly because high accuracy is required to estimate (relative) binding affinities. For low-to medium-throughput in silico screening, (e.g., scoring and prioritizing a series of inhibitors sharing the same molecular scaffold) efficient approximations have been developed in the past decade, like linear scaling QM in which the computation time scales almost linearly with the number of basis functions. Furthermore, QM-based procedures have been used recently for determining protonation states of ionizable groups, evaluating energies, and optimizing molecular structures. For high-throughput in silico screening QM approaches have been employed to derive robust quantitative structure-activity relationship models. It is expected that the use of QM methods will keep growing in all phases of computer-aided drug design and development. However, extensive sampling of conformational space and treatment of solution of macromolecules are still limiting factors for the broad application of QM in drug design.

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A Quantum Mechanics/Molecular Mechanics Study of the Protein−Ligand Interaction of Two Potent Inhibitors of Human O-GlcNAcase: PUGNAc and NAG-Thiazoline

Abstract: compounds with more interesting inhibitory activity on the basis of its three-dimensional structure.

Cited by 27 publications

References 32 publications

Enzymatic Molecular Mechanism of the Human O-GlcNAcase to Design New Inhibitors: A Quantum Mechanical Approach

Enzymatic Molecular Mechanism of the Human O-GlcNAcase to Design New Inhibitors: A Quantum Mechanical Approach

Virtual Screening and Molecular Dynamics Simulations from a Bank of Molecules of the Amazon Region Against Functional NS3-4A Protease-Helicase Enzyme of Hepatitis C Virus

Quantum Mechanical Methods for Drug Design

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