Influence of Protonation on Substrate and Inhibitor Interactions at the Active Site of Human Monoamine Oxidase-A

Zapata‐Torres, Gerald; Fierro, Angélica; Miranda-Rojas, Sebastián; Guajardo, Carlos D; Sáez-Briones, Patricio; Salgado, J. Cristian; Celis-Barros, Cristián

doi:10.1021/ci300081w

Cited by 11 publications

(12 citation statements)

References 35 publications

(60 reference statements)

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“…As mentioned above, numerous methods were developed to determine the most optimized exit tunnels for inhibitors including Caver 2.1, MOLE 2.0, and MolAxis . All of these packages have highly been appropriated and validated over many previous studies . Therefore, in the present work, the unbinding tunnels are predicted using all three methods, and then three individual orientations are described in Supporting Information Figure S1.…”

Section: Resultsmentioning

confidence: 99%

“…As the pulling pathway is known to be sensitive in the evaluation of binding affinity using non‐equilibrium MD simulations, the Caver 2.1, MOLE 2.0, and MolAxis are used to determine the proper pulling pathway, which have popularly been applied in several previous studies . These detected pulling pathways are approximately the same (Supporting Information Figure S1).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Fast and accurate determination of the relative binding affinities of small compounds to HIV-1 protease using non-equilibrium work

2016

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The fast pulling ligand (FPL) out of binding cavity using non-equilibrium molecular dynamics (MD) simulations was demonstrated to be a rapid, accurate and low CPU demand method for the determination of the relative binding affinities of a large number of HIV-1 protease (PR) inhibitors. In this approach, the ligand is pulled out of the binding cavity of the protein using external harmonic forces, and the work of pulling force corresponds to the relative binding affinity of HIV-1 PR inhibitor. The correlation coefficient between the pulling work and the experimental binding free energy of R=-0.95 shows that FPL results are in good agreement with experiment. It is thus easier to rank the binding affinities of HIV-1 PR inhibitors, that have similar binding affinities because the mean error bar of pulling work amounts to δW=7%. The nature of binding is discovered using the FPL approach. © 2016 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Fast and accurate determination of the relative binding affinities of small compounds to HIV-1 protease using non-equilibrium work

2016

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“…21 On the other hand, for MAO substrates, although the cationic species is dominant under physiological conditions, an active site which is not at all hydrophobic favours the unprotonated state in agreement with our previous results, indicating that a neutral substrate is needed for the reaction to take place. 16 During the catalytic reductive half-reaction, the Cα-Hα bond of substrates is oxidatively cleaved to form a protonated imine intermediate. Then, the reduced cofactor is reoxidised to its functional form by molecular oxygen, followed by the releas of hydrogen peroxide during the oxidative half-reaction.…”

mentioning

confidence: 99%

Revealing Monoamine Oxidase B Catalytic Mechanisms by Means of the Quantum Chemical Cluster Approach

Zapata‐Torres

Fierro

Barriga-González

et al. 2015

J. Chem. Inf. Model.

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Two of the possible catalytic mechanisms for neurotransmitter oxidative deamination by monoamine oxidase B (MAO B), namely, polar nucleophilic and hydride transfer, were addressed in order to comprehend the nature of their rate-determining step. The Quantum Chemical Cluster Approach was used to obtain transition states of MAO B complexed with phenylethylamine (PEA), benzylamine (BA), and p-nitrobenzylamine (NBA). The choice of these amines relies on their importance to address MAO B catalytic mechanisms so as to help us to answer questions such as why BA is a better substrate than NBA or how para-substitution affects substrate's reactivity. Transition states were later validated by comparison with the experimental free energy barriers. From a theoretical point of view, and according to the our reported transition states, their calculated barriers and structural and orbital differences obtained by us among these compounds, we propose that good substrates such as BA and PEA might follow the hydride transfer pathway while poor substrates such as NBA prefer the polar nucleophilic mechanism, which might suggest that MAO B can act by both mechanisms. The low free energy barriers for BA and PEA reflect the preference that MAO B has for hydride transfer over the polar nucleophilic mechanism when catalyzing the oxidative deamination of neurotransmitters.

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“…Examples of simulation problem domains that have benefited from multigrid techniques include porous media transport [10,11], molecular dynamics [12][13][14], fluid dynamics [10,11,15], and neural network simulations (and neurotransmitter diffusion) [16].…”

Section: Historymentioning

confidence: 99%

“…The unknown vector and right-hand side of Equation 13 can now be replaced with new variables, revealing a new problem with only N H unknowns, down from the N h unknowns in Equation 12.…”

Section: Coarse Solutionmentioning

confidence: 99%

OpenMG: A new multigrid implementation in Python

Bertalan

Islam

Sidje

et al. 2014

Numer. Linear Algebra Appl.

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SUMMARYIn many large-scale computations, systems of equations arise in the form Au D b, where A is a linear operation to be performed on the unknown data u, producing the known right-hand side, b, which represents some constraint of known or assumed behavior of the system being modeled. Because such systems can be very large, solving them directly can be too slow. In contrast, a multigrid method removes different components of the error at different resolutions using smoothers that reduce high-frequency components of the error more readily than low. Here, we present an open-source multigrid solver written only in Python. OpenMG is a pure Python experimentation environment for testing multigrid concepts, not a production solver. The particular restriction method implemented is for 'standard' multigrid. By making the code simple and modular, we make the algorithmic details clear. The resulting solver is tested on an implicit pressure reservoir simulation problem with satisfactory results.

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Influence of Protonation on Substrate and Inhibitor Interactions at the Active Site of Human Monoamine Oxidase-A

Cited by 11 publications

References 35 publications

Fast and accurate determination of the relative binding affinities of small compounds to HIV-1 protease using non-equilibrium work

Fast and accurate determination of the relative binding affinities of small compounds to HIV-1 protease using non-equilibrium work

Revealing Monoamine Oxidase B Catalytic Mechanisms by Means of the Quantum Chemical Cluster Approach

OpenMG: A new multigrid implementation in Python

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