Docking and molecular dynamics studies of peripheral site ligand–oximes as reactivators of sarin-inhibited human acetylcholinesterase

Almeida, Joyce S. F. D. de; Cuya, Teobaldo; Guimarães, Ana P.; Ramalho, Teodorico C.; Gonçalves, Arlan da Silva; Koning, Martijn C. de; França, Tanos C. C.

doi:10.1080/07391102.2015.1124807

Cited by 25 publications

(13 citation statements)

References 24 publications

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“…Sequence alignment showed that PpAChE5 possessed most of the crucial structure features of AChEs family, including the important choline binding sites, catalytic triads functioning as a charge-relay system, a number of aromatic residues lining the catalytic gorge and six cysteine residues forming three intramolecular disulphide bridges. These conserved amino acids have been reported to play important roles in AChE functions [ 14 ]. However, this putative AChE also has some unique features, such as the ‘AGESAG’ instead of ‘FGESAG’ and only seven out of fourteen aromatic residues are conserved.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Fifth Putative Acetylcholinesterase in the Wolf Spider, Pardosa pseudoannulata

Meng

Bao

et al. 2017

Molecules

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Background: Acetylcholinesterase (AChE) is an important neurotransmitter hydrolase in invertebrate and vertebrate nervous systems. The number of AChEs is various among invertebrate species, with different functions including the ‘classical’ role in terminating synaptic transmission and other ‘non-classical’ roles. Methods: Using rapid amplification of cDNA ends (RACE) technology, a new putative AChE-encoding gene was cloned from Pardosa pseudoannulata, an important predatory natural enemy. Sequence analysis and in vitro expression were employed to determine the structural features and biochemical properties of this putative AChE. Results: The cloned AChE contained the most conserved motifs of AChEs family and was clearly clustered with Arachnida AChEs. Determination of biochemical properties revealed that the recombinant enzyme had the obvious preference for the substrate ATC (acetylthiocholine iodide) versus BTC (butyrylthiocholine iodide). The AChE was highly sensitive to AChE-specific inhibitor BW284C51, but not butyrylcholinesterase-specific inhibitor tetraisopropyl pyrophosphoramide (ISO-OMPA). Based on these results, we concluded that a new AChE was identified from P. pseudoannulata and denoted as PpAChE5. Conclusion: Here we report the identification of a new AChE from P. pseudoannulata and increased the AChE number to five in this species. Although PpAChE5 had the biggest Vmax value among five identified AChEs, it showed relatively low affinity with ATC. Similar sensitivity to test insecticides indicated that this AChE might serve as the target for both organophosphorus and carbamate insecticides.

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Section: Discussionmentioning

confidence: 99%

Characterization of the Fifth Putative Acetylcholinesterase in the Wolf Spider, Pardosa pseudoannulata

Meng

Bao

et al. 2017

Molecules

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“…5HF9 corresponds to the crystallographic structure of Hss AChE inhibited by POX and complexed with HI-6. This experimental structure was opened in the Discovery Studios ® Visualizer (DS ® Vis) 4.5 program [20], and had the missing loops PGGTGG and PKA and the C-terminal sequence EGR built through alignment to its FASTA sequence (code P22303) obtained from the Uniprot server (), following the same procedure adopted before [21], in order to obtain a complete model for the complex Hss AChE/POX. 4B0O corresponds to the crystallographic structure of Hss BChE inhibited by soman and complexed with benzyl pyridinium-4-methyltrichloroacetimidate (BP4M).…”

Section: Methodsmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon

et al. 2018

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Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes”) depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153) with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens) AChE (HssACHE) and BChE (HssBChE) inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate). According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results.

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“…The complexes Ee AChE-POX/oxime were simulated using GROMACS 5.1.4 [ 68 ] package in a cubic box (941.59 nm 3 ) containing approximated 28,522 spc216 water molecules with periodic boundary conditions. The minimization steps were steepest descent with position restrained (PR) of ligands and protein, with a convergence criterion of 100.00 Kcal/mol.Å, steepest descent without PR to flexibilize the system, conjugate gradients (CG), and L-BFGS (limited-memory Broyden–Fletcher–Goldfarb–Shanno [ 24 ]), until a minimum of energy of 1.00 Kcal/mol.Å. After that, two steps of equilibration were done.…”

Section: Methodsmentioning

confidence: 99%

“…For this reason, studies are focused on looking for oximes that could be efficient against a larger number of OPs, conjugated with an appropriate penetration in the BBB. In this sense, neutral oximes ( Figure 2 ) have been proposed and studied by several authors [ 11 , 18 , 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Modeling and In Vitro Studies of a Neutral Oxime as a Potential Reactivator for Acetylcholinesterase Inhibited by Paraoxon

et al. 2018

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The present work aimed to compare the small, neutral and monoaromatic oxime, isatin-3-oxime (isatin-O), to the commercial ones, pralidoxime (2-PAM) and obidoxime, in a search for a new potential reactivator for acetylcholinesterase (AChE) inhibited by the pesticide paraoxon (AChE/POX) as well as a novel potential scaffold for further synthetic modifications. The multicriteria decision methods (MCDM) allowed the identification of the best docking poses of those molecules inside AChE/POX for further molecular dynamic (MD) studies, while Ellman’s modified method enabled in vitro inhibition and reactivation assays. In corroboration with the theoretical studies, our experimental results showed that isatin-O have a reactivation potential capable of overcoming 2-PAM at the initial moments of the assay. Despite not achieving better results than obidoxime, this molecule is promising for being an active neutral oxime with capacity of crossing the blood–brain barrier (BBB), to reactivate AChE/POX inside the central and peripheral nervous systems. Moreover, the fact that isatin-O can also act as anticonvulsant makes this molecule a possible multipotent reactivator. Besides, the MCDM method showed to be an accurate method for the selection of the best docking poses generated in the docking studies.

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Docking and molecular dynamics studies of peripheral site ligand–oximes as reactivators of sarin-inhibited human acetylcholinesterase

Cited by 25 publications

References 24 publications

Characterization of the Fifth Putative Acetylcholinesterase in the Wolf Spider, Pardosa pseudoannulata

Characterization of the Fifth Putative Acetylcholinesterase in the Wolf Spider, Pardosa pseudoannulata

Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon

Molecular Modeling and In Vitro Studies of a Neutral Oxime as a Potential Reactivator for Acetylcholinesterase Inhibited by Paraoxon

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