The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents
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2019
Authors
Vitorović-Todorović, Maja D.Worek, Franz
Perdih, Andrej
Bauk, Sonja Đ.
Vujatović, Tamara B.
Cvijetić, Ilija
Article (Published version)
Metadata
Show full item recordAbstract
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.
Keywords:
Acetylcholinesterase / Irreversible inhibition / Molecular dynamics simulations / Nerve agents / Pre-treatment / ProtectionSource:
Chemico-Biological Interactions, 2019, 309Publisher:
- Elsevier
Funding / projects:
- Rational design and synthesis of biologically active and coordination compounds and functional materials, relevant for (bio)nanotechnology (RS-MESTD-Basic Research (BR or ON)-172035)
- Ministry of Higher Education, Science and Technology of the Republic of Slovenia through Grant P1-0012
Note:
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3301
DOI: 10.1016/j.cbi.2019.06.027
ISSN: 0009-2797; 0009-2797
WoS: 000482178500022
Scopus: 2-s2.0-85067692699
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Institution/Community
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Vitorović-Todorović, Maja D. AU - Worek, Franz AU - Perdih, Andrej AU - Bauk, Sonja Đ. AU - Vujatović, Tamara B. AU - Cvijetić, Ilija PY - 2019 UR - https://cherry.chem.bg.ac.rs/handle/123456789/3300 AB - 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. PB - Elsevier T2 - Chemico-Biological Interactions T1 - The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents VL - 309 DO - 10.1016/j.cbi.2019.06.027 ER -
@article{ author = "Vitorović-Todorović, Maja D. and Worek, Franz and Perdih, Andrej and Bauk, Sonja Đ. and Vujatović, Tamara B. and Cvijetić, Ilija", year = "2019", 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.", publisher = "Elsevier", journal = "Chemico-Biological Interactions", title = "The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents", volume = "309", doi = "10.1016/j.cbi.2019.06.027" }
Vitorović-Todorović, M. D., Worek, F., Perdih, A., Bauk, S. Đ., Vujatović, T. B.,& Cvijetić, I.. (2019). The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents. in Chemico-Biological Interactions Elsevier., 309. https://doi.org/10.1016/j.cbi.2019.06.027
Vitorović-Todorović MD, Worek F, Perdih A, Bauk SĐ, Vujatović TB, Cvijetić I. The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents. in Chemico-Biological Interactions. 2019;309. doi:10.1016/j.cbi.2019.06.027 .
Vitorović-Todorović, Maja D., Worek, Franz, Perdih, Andrej, Bauk, Sonja Đ., Vujatović, Tamara B., Cvijetić, Ilija, "The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents" in Chemico-Biological Interactions, 309 (2019), https://doi.org/10.1016/j.cbi.2019.06.027 . .