Knowledge Bank

Organophosphorus compounds (OPs) are widely implemented as chemical nerve agents and pesticides. These OPs bond to and inhibit a catalytic residue, Ser-203, in the enzyme acetylcholinesterase (AChE), which is responsible for the hydrolysis of acetylcholine. After exposure to OPs, AChE is initially inhibited for a period of time followed by an aging process, wherein the inhibited Ser-203 residue dealkylates and forms a stable phosphonate anion in the active site. There are known treatments for inhibited AChE in the form of therapeutic oximes, but no treatments for aged AChE currently exist. If left untreated, acetylcholine will build up in the central nervous system. Previous research has demonstrated quinone methides (QMs) to realkylate phosphonates and other biological molecules, which makes QMs a good candidate for an aged AChE realkylator. Previous efforts have resulted in a lead compound in the form of a quinone methide precursor (QMP). This research studies the potential of new QMPs and QMP-like compounds to realkylate the stable phosphonate anion on Ser-203 in aged AChE and allow for subsequent reactivation. With computational methods, libraries 5-member ring QMP-like compounds were tested to determine their affinity for the aged AChE active site as potential realkylators. Molecular Docking with subsequent Molecular Dynamics were used to determine compounds that favored the aged AChE active site and to elucidate the important interactions between the proposed realkylators and AChE. It was determined that substituted pyrrole based realkylators demonstrate a higher affinity for the aged active site that previously studies compounds and show promise as potential realkylators. Leaving group and charge state trends were also studied.