Computational Studies to Understand Various Pre- and Post-Treatments of Organophosphorus Poisoning.

다국어 초록 (Multilingual Abstract)

Multiple computational chemistry methods were applied to study several strategies in the treatment for organophosphorus (OP) nerve agents. OP toxicity is brought about by covalent inhibition of acetylcholinesterase (AChE), leading to a buildup of the neurotransmitter acetylcholine at your nerve endings, resulting in a host of symptoms known as a "cholinergic crisis." There has been ongoing focus on AChE in academic and industrial settings because of its rapid catalysis rates as well as treatment for OP exposure. A sister enzyme to AChE, butyrylcholinesterase (BChE) is most commonly found in blood plasma and has the same innate ability to hydrolyze acetylcholine, but BChE has less substrate specificity and is more efficient in the hydrolysis of butyrylcholine. In this thesis, various methods will be investigated to evaluate treatment options in scenarios for pre- and post-exposure to OP compounds with AChE and BChE.As a prophylactic, pre-treatment for OP exposure, BChE reacts stoichiometrically with OP nerve agents and has shown the ability to be a catalytic bioscavenger with select mutations. Recombinant or mutated forms of BChE have shown the ability to catalytically degrade OP compounds before inhibition of AChE. Molecular dynamics simulations of a recently investigated Y282N/G283H/T284M/P285L variant of BChE in its native and inhibited forms were performed. Intriguingly, while previous recombinant forms of BChE had mutations located at the S-H-E catalytic triad, these mutations were in the acyl binding pocket. By investigating the conformational dynamics of the recombinant BChE variant, possible mechanisms for the hydrolysis of OP-inhibited BChE by activation of a nucleophilic water were explored.Having presented a possible catalytic bioscavenger in the form of a recombinant BChE, we applied the knowledge of molecular dynamics to studying possible artificial scavengers of OP agents. Basket molecules have previously been implicated for the decontamination of OP compounds by precipitation. Using ab initio methods, a novel molecular basket as a supramolecular assembly was studied in the binding of tetrahalomethane guest molecules. In addition to the complex process of binding, the basket observed two rapidly interconverting conformers (termed, B(+) and B(-)). Utilizing molecular dynamics, four rapidly interconverting states B(+), B(-), CX4⊂B(+), and CX4⊂B(--) were identified. Employing ab initio methods, coupled with nudged elastic band advanced interpolation scheme, rates for all possible interconversion pathways were calculated. Evaluation of two mechanistic alternatives to molecular recognition were performed: conformational selection or induced fit. Fundamental studies of molecular recognition in host - guest chemistry is useful in developing stereospecific artificial scavengers of guests.FDA-approved treatments for post-OP exposure involve oximes that can treat the OP-inhibited form of AChE. However, after prolonged exposure with no treatment, phosphylation is followed by aging (dealkylation) of the phosphylated serine residue. There is no effective treatment for the aged form of the enzyme. Our group has generated quinone methide precursors (QMPs) with the ability to treat the aged form of the enzyme. As alkylating agents, QMPs can effectively ?resurrect? the aged form of the enzyme. However, the mechanism of action of our QMPs is still unknown. With quantum mechanical/molecular mechanical (QM/MM) methods, several docked orientations of a QMP were evaluated at high levels of theory. Further understanding of the non-covalent interactions for each binding element of the QMP will be able to guide the synthesis of more active QMP frameworks.