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The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents.
- Source :
-
Chemico-biological interactions [Chem Biol Interact] 2019 Aug 25; Vol. 309, pp. 108714. Date of Electronic Publication: 2019 Jun 19. - Publication Year :
- 2019
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Abstract
- Acetylcholinesterase (AChE) is an enzyme which terminates the cholinergic neurotransmission, by hydrolyzing acetylcholine at the nerve and nerve-muscle junctions. The reversible inhibition of AChE was suggested as the pre-treatment option of the intoxications caused by nerve agents. Based on our derived 3D-QSAR model for the reversible AChE inhibitors, we designed and synthesized three novel compounds 8-10, joining the tacrine and aroylacrylic acid phenylamide moieties, with a longer methylene chain to target two distinct, toplogically separated anionic areas on the AChE. The targeted compounds exerted low nanomolar to subnanomolar potency toward the E. eel and human AChE's as well as the human BChE and showed mixed inhibition type in kinetic studies. All compounds were able to slow down the irreversible inhibition of the human AChE by several nerve agents including tabun, soman and VX, with the estimated protective indices around 5, indicating a valuable level of protection. Putative noncovalent interactions of the selected ligand 10 with AChE active site gorge were finally explored by molecular dynamics simulation suggesting a formation of the salt bridge between the protonated linker amino group and the negatively charged Asp74 carboxylate side chain as a significant player for the successful molecular recognition in line with the design strategy. The designed compounds may represent a new class of promising leads for the development of more effective pre-treatment options.<br /> (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Subjects :
- Acetylcholinesterase chemistry
Acetylcholinesterase metabolism
Binding Sites
Catalytic Domain
Chemical Warfare Agents metabolism
Cholinesterase Inhibitors metabolism
Cholinesterases chemistry
Humans
Kinetics
Molecular Dynamics Simulation
Organophosphorus Compounds chemistry
Organophosphorus Compounds metabolism
Protective Agents metabolism
Quantitative Structure-Activity Relationship
Soman chemistry
Soman metabolism
Chemical Warfare Agents chemistry
Cholinesterase Inhibitors chemistry
Cholinesterases metabolism
Protective Agents chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7786
- Volume :
- 309
- Database :
- MEDLINE
- Journal :
- Chemico-biological interactions
- Publication Type :
- Academic Journal
- Accession number :
- 31228470
- Full Text :
- https://doi.org/10.1016/j.cbi.2019.06.027