Design of electron-donating group substituted 2-PAM analogs as antidotes for organophosphate insecticide poisoning

Abstract

Design of novel 2-pralidoxime analogs by incorporating electron-donating groups onto its pyridinium core to enhance blood–brain barrier permeability and binding susceptibility toward acetylcholinesterase with paraoxon bound.

Preferential Door for Ligand Binding and Unbinding Pathways in Inhibited Human Acetylcholinesterase

“…After 2-PAM approached S203-POX, the distance between the oxime of the O atom (−CNOH) of this ligand and the P atom of POX, denoted as d OP , was observed to be approximately 3.32 ± 0.33 Å (Figure b and Table S2). The observed value of d OP aligns with recently reported findings that delineate an optimal distance based on a 2D free energy landscape (FEL), as revealed through an enhanced sampling method called DS-MD simulation . This 2D FEL demonstrated two discernible binding modes, characterized by the angle between the O atom of its oxime group, the P atom of S203-POX, and the O atom of S203, referred to as θ OPO .…”

“…The observed value of d OP aligns with recently reported findings that delineate an optimal distance based on a 2D free energy landscape (FEL), as revealed through an enhanced sampling method called DS-MD simulation. 12 This 2D FEL demonstrated two discernible binding modes, characterized by the angle between the O atom of its oxime group, the P atom of S203-POX, and the O atom of S203, referred to as θ OPO . The predominant binding mode was identified as an (α) in-line conformation (with 120°< θ OPO < 180°), constituting 63.79% ± 6.83%, while the less prevalent binding mode assumed an (β) adjacent conformation (with θ OPO < 120°), 13 comprising 36.00% ± 6.75% based on bootstrap analysis (Table S2 and Figure S2).…”

Combined Transcriptomics and Metabolomics Analysis Reveals Profenofos-Induced Invisible Injury in Pakchoi (Brassica rapa L.) through Inhibition of Carotenoid Accumulation

“…8,9 Organophosphorus insecticides (OPi) are among the most versatile and widely used insecticides and account for approximately 30% of the global pesticide market. 10 OPi kill insects by inhibiting acetylcholinesterase activity and blocking nerve conduction 11 and may have detrimental effects on crops. Studies have reported that chlorpyrifos can induce oxidative stress to affect the normal metabolism of rice and inhibit its growth.…”

“…For example, pyrethroid pesticides, such as permethrin and cypermethrin, interfere with the growth and yield of maize, and imidacloprid, a neonicotinoid insecticide, causes metabolic disorders in garlic and bean plants. , Organophosphorus insecticides (OPi) are among the most versatile and widely used insecticides and account for approximately 30% of the global pesticide market . OPi kill insects by inhibiting acetylcholinesterase activity and blocking nerve conduction and may have detrimental effects on crops. Studies have reported that chlorpyrifos can induce oxidative stress to affect the normal metabolism of rice and inhibit its growth. , Generally, visible symptoms of damage, such as leaf chlorosis and plant wilting which indicate varying degrees of toxicity to the plant, are used to evaluate the toxicological effects of pollutants on plants .…”