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A Computational Investigation Into the Development of an Effective Therapeutic Against Organophosphorus Nerve Agent Exposure

Brown, Jason David
http://rave.ohiolink.edu/etdc/view?acc_num=osu1416836502

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Chemistry.
Organophosphorus (OP) nerve agents are a very toxic class of compounds for which there is a great need of effective therapeutics. OPs are phosphoryl-containing compounds typically used as pesticides, but they have been used as chemical warfare agents. Their toxicity is derived from the inhibition of acetylcholinesterase (AChE), an enzyme found in the human body that regulates levels of the neurotransmitter acetylcholine. OPs inhibit AChE by undergoing nucleophilic attack by the catalytic Ser203 residue. A water molecule is not sufficiently nucleophilic to attack the phosphoryl center to regenerate functional AChE, so addition of a stronger nucleophile, such as an oxime, is utilized for attack at the phosphoryl center and cleavage of the P–O(Ser203) bond to reactivate AChE. However, a second reaction occurs in the inhibition process, called "aging," in which the phosphoryl O-alkyl functionality is dealkylated, creating an anionic species in the active site. There is currently no treatment after aging has occurred, as oximes can no longer attack the phosphoryl center to reactivate AChE. This dissertation encompasses some of the work that has been done on two of the possible routes for treatment after OP exposure. The first route involves utilizing a supramolecular compound that is capable of binding and hydrolyzing the toxic OPs before inhibition of AChE can occur, while the second method attempts to realkylate the aged form of AChE, through use of a selective alkylating agent to replace the departed alkyl group of the OP with a new alkyl group. Gated molecular baskets, with a dynamic mode of action, are offered as models for examining the encapsulation and degradation of toxic OPs. In an effort to understand the binding of OPs to the molecular baskets, we developed a computational protocol for examining the dynamics of the hosts and host-guest interactions through molecular dynamics and docking calculations. We found that modifying the functionality of the baskets can have a profound impact on the ability to trap OP guests. Specifically, the computational results of functionalized molecular baskets correlate with experimental studies in that the size and electronic effects of both the baskets and the guests determine the degree of OP encapsulation, suggesting that these molecular baskets could be utilized for efficient and selective encapsulation, detection, and detoxification of toxic organophosphorus nerve agents. For the realkylation of OP-aged AChE, an efficient alkylating agent must be developed. One such alkylating agent, quinone methides (QMs), could possibly be utilized as they have previously been shown to have highly tunable reactivity and could be administered in an unreactive prodrug form. The naphthalene and quinoline scaffolds were selected for incorporation of the QM moiety and were subjected to a computational study. We found that these naphthyl and quinoline-based QM precursors displayed a variety of reaction energetics in the alkylation of model nucleophiles, with some of the proposed compounds exhibiting particularly encouraging docking results with human AChE. As such, we have selected possible lead compounds from the computational study to be synthesized and investigated experimentally for the goal of realkylating OP-aged AChE.
Christopher Hadad, PhD (Advisor)
Jovica Badjic, PhD (Committee Member)
Jonathan Parquette, PhD (Committee Member)
Thomas Santner, PhD (Committee Member)
Chemistry; Organic Chemistry
organophosphorus; nerve agents; acetylcholinesterase; AChE; molecular baskets; quinone methide; encapsulation; molecular recognition; molecular dynamics; docking; sarin; soman; naphthoquinone methide; quinoline quinone methide

Recommended Citations

Citations

  • Brown, J. D. (2014). A Computational Investigation Into the Development of an Effective Therapeutic Against Organophosphorus Nerve Agent Exposure [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1416836502

    APA Style (7th edition)

  • Brown, Jason. A Computational Investigation Into the Development of an Effective Therapeutic Against Organophosphorus Nerve Agent Exposure. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1416836502.

    MLA Style (8th edition)

  • Brown, Jason. "A Computational Investigation Into the Development of an Effective Therapeutic Against Organophosphorus Nerve Agent Exposure." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1416836502

    Chicago Manual of Style (17th edition)

osu1416836502
121
© 2014, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.