First principles calculations of thermodynamics and kinetic parameters and molecular dynamics simulations of acetylcholinesterase reactivators: can mouse data provide new insights into humans?

Matos, Karina Silvia; Cunha, Elaine F. F. da; Gonçalves, Arlan da Silva; Wilter, Alan; Kuča, Kamil; França, Tanos C. C.; Ramalho, Teodorico C.

doi:10.1080/07391102.2012.687521

Cited by 18 publications

(6 citation statements)

References 67 publications

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“…It terminates synaptic signals by rapidly hydrolyzing neurotransmitter acetylcholine (ACh) with a rate close to the diffusion-controlled limit 1–3 . The catalytic site of AChE is buried at the bottom of a 20 Å deep, narrow and highly electronegative catalytic gorge 4–6 and its catalytic triad (Ser200, His440 and Glu327) as well as its oxyanion hole (peptidic NH groups of Gly118, Gly119, and Ala201) are typical of serine hydrolyses. (Torpedo californica AChE residue numbering is used throughout this paper.)…”

Section: Introductionmentioning

confidence: 99%

Aging Mechanism of Soman Inhibited Acetylcholinesterase

et al. 2012

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Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nervous system that hydrolyses neurotransmitter acetylcholine (ACh) and terminates synaptic signals. The catalytic serine of AChE can be phosphonylated by soman, one of the most potent nerve agents, and subsequently undergo an aging reaction. This phosphonylation and aging process leads to irreversible AChE inhibition, results in accumulation of excess ACh at the synaptic clefts and causes neuromuscular paralysis. By employing Born-Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the aging mechanism of soman phosphonylated AChE and determined its free energy profile. This aging reaction starts with the scission of the O2-Cα bond, which is followed by methyl migration, and results in a tertiary carbenium intermediate. At the transition state, the scissile O2-Cα bond is already cleaved with an average O-C distance of 3.2 ± 0.3 Å and the migrating methyl group is shared between Cα and Cβ carbons with C-C distances of 1.9 ± 0.1 and 1.8 ± 0.1 Å, respectively. The negatively charged phosphonate group is stabilized by a salt bridge with the imidazole ring of the catalytic histidine. A major product of aging, 2,3-dimehtyl-2-butanol can be formed swiftly by the reaction of a water molecule. Our characterized mechanism and simulation results provide new detailed insights into this important biochemical process.

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Section: Introductionmentioning

confidence: 99%

Aging Mechanism of Soman Inhibited Acetylcholinesterase

et al. 2012

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“…Despite there are still no experimental data on the metabolism of the C60 derivatives reported by Shoji et al (2013) available in literature, Tzoupis et al (2011) have estimated in a theoretical work that their ADMET (absorption, distribution, metabolism, excretion and toxicity) are promising. Furthermore, it is important to note that C60-3 and C60-4 may also interact with HssAChE active site because they have the same pyridine ring of Pralidoxime (an oxime used as antidote against intoxication by organophosphorous compounds) (Gonçalves, França, Caetano & Ramalho, 2014;Matos et al, 2012;Gonçalves, França, Figueroa-Villar & Pascutti, 2011;Ramalho, França, Rennó, Guimarães, Cunha & Kuca, 2010;Gonçalves, França, Silva & Figueroa-Villar, 2006). …”

Section: Dockingmentioning

confidence: 99%

Computational studies of acetylcholinesterase complexed with fullerene derivatives: a new insight for Alzheimer disease treatment

Gonçalves

França

Oliveira

2015

Journal of Biomolecular Structure and Dynamics

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Here, we propose five fullerene (C60) derivatives as new drugs against Alzheimer's disease (AD). These compounds were designed to act as new human acetylcholinesterase (HssAChE) inhibitors by blocking its fasciculin II (FASII) binding site. Docking and molecular dynamic results show that our proposals bind to the HssAChE tunnel entrance, forming stable complex, and further binding free energy calculations suggest that three of the derivatives proposed here could be potent HssAChE inhibitors. We found a region formed by a set of residues (Tyr72, Asp74, Trp286, Gln291, Tyr341, and Pro344) which can be further exploited in the drug design of new inhibitors of HssAChE based on C60 derivatives. Results presented here report for the first time by a new class of molecules that can become effective drugs against AD.

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“…Regular transmission of these inputs is directly related to the action of acetylcholinesterase (AChE), an enzyme present in the neuromuscular junctions and responsible for the hydrolysis of the neurotransmitter acetylcholine. In some neurodegenerative disorders, like myastimiahenia gravis or Parkinson's disease, inhibition of AChE is a fundamental therapeutic step [1,3].…”

Section: Introductionmentioning

confidence: 99%

Molecular Modeling Studies of Piperidine Derivatives as New Acetylcholinesterase Inhibitors against Neurodegenerative Diseases

Cunha

Resende

França

et al. 2013

Journal of Chemistry

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Neurodegenerative disorders are related to the progressive loss of structure or function and, eventually, death of neurons. These processes are responsible for diseases like Parkinson's, Alzheimer's, and Huntington's, and the main molecular target for the drug design against these illnesses today is the enzyme acetylcholinesterase (AChE). Following this line, in the present work, we applied docking techniques to study some piperidine derivative inhibitors of AChE and further propose structures of six new AChE inhibitors as potential new drugs against neurodegenerative disorders. The best inhibitor proposed was submitted to additional molecular dynamics simulations steps.

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First principles calculations of thermodynamics and kinetic parameters and molecular dynamics simulations of acetylcholinesterase reactivators: can mouse data provide new insights into humans?

Cited by 18 publications

References 67 publications

Aging Mechanism of Soman Inhibited Acetylcholinesterase

Aging Mechanism of Soman Inhibited Acetylcholinesterase

Computational studies of acetylcholinesterase complexed with fullerene derivatives: a new insight for Alzheimer disease treatment

Molecular Modeling Studies of Piperidine Derivatives as New Acetylcholinesterase Inhibitors against Neurodegenerative Diseases

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