The in vitro protective effects of the three novel nanomolar reversible inhibitors of human cholinesterases against irreversible inhibition by organophosphorous chemical warfare agents. (25th August 2019)

• Record Type: Journal Article
• Authors: Vitorović-Todorović, Maja D.; Worek, Franz; Perdih, Andrej; Bauk, Sonja Đ.; Vujatović, Tamara B.; Cvijetić, Ilija N.
• Is Part Of: Chemico-biological interactions. Volume 309(2019)
• Publication Date: 2019-08-25
• Subjects: Acetylcholinesterase -- Irreversible inhibition -- Nerve agents -- Protection -- Pre-treatment -- Molecular dynamics simulations; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2019.06.027
• Languages: English
• ISSNs: 0009-2797

Abstract

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 compounds8-10, 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 ligand10 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. Graphical abstract: Image 1 Highlights: Novel low nanomolar to subnanomolar inhibitors of hAChE have been synthesized. Compounds protected AChE from irreversible inhibition by nerve agents. The interactions of the compound10 and AChE are investigated by MD simulations.