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wright1278010674.pdf (692.54 KB)
ETD Abstract Container
Abstract Header
Quantitative Structure-Activity Relationships for Organophosphates Binding to Trypsin and Chymotrypsin
Author Info
Ruark, Christopher Daniel
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=wright1278010674
Abstract Details
Year and Degree
2010, Master of Science (MS), Wright State University, Pharmacology and Toxicology.
Abstract
Organophosphate (OP) nerve agents such as sarin, soman, tabun, and O-ethyl S-[2-(diisopropylamino) ethyl] methylphosphonothioate (VX) do not react solely with acetylcholinesterase (AChE). Evidence suggests that a wide range of cholinergic-independent pathways are also targeted, including serine proteases. These proteases comprise nearly one-third of all known proteases and play major roles in synaptic plasticity, learning, memory, neuroprotection, wound healing, cell signaling, inflammation, blood coagulation and protein processing. Inhibition of these proteases by OPs was found to exert a wide range of noncholinergic effects depending on the type of OP, the dose, and the duration of exposure. Consequently, in order to understand these differences, in silico biologically-based dose-response and quantitative structure-activity relationship (QSAR) methodologies need to be integrated. Here, QSARs were used to predict OP bimolecular rate constants for trypsin and α-chymotrypsin. A heuristic regression of over 500 topological/constitutional, geometric, thermodynamic, electrostatic, and quantum mechanical descriptors, using the software Ampac 8.0 and Codessa 2.51 (SemiChem, Inc., Shawnee, KS), was developed to obtain statistically verified equations for the models. General models, using all data subsets, resulted in R
2
values of 0.94 and 0.92 and leave-one-out Q
2
values of 0.9 and 0.87 for trypsin and α-chymotrypsin. To validate the general model, training sets were split into independent subsets for test set evaluation. A y-randomization procedure, used to estimate chance correlation, was performed 10,000 times resulting in mean R
2
values of 0.24 and 0.3 for trypsin and α-chymotrypsin. The results show that these models are highly predictive and capable of delineating the complex mechanism of action between OPs and serine proteases, and ultimately, by applying this approach to other OP enzyme reactions such as AChE, facilitate the development of biologically based dose response models.
Committee
Jeffery Gearhart, PhD (Committee Chair)
James Lucot, PhD (Committee Co-Chair)
Peter Robinson, PhD (Committee Member)
Mariana Morris, PhD (Other)
John Bantle, PhD (Other)
Pages
84 p.
Subject Headings
Toxicology
Keywords
Quantitative structure activity relationship
;
QSAR
;
Trypsin
;
Chymotrypsin
;
Physiologically based pharmacokinetic
;
Biologically based dose response
;
Organophosphates
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Refworks
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Citations
Ruark, C. D. (2010).
Quantitative Structure-Activity Relationships for Organophosphates Binding to Trypsin and Chymotrypsin
[Master's thesis, Wright State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=wright1278010674
APA Style (7th edition)
Ruark, Christopher.
Quantitative Structure-Activity Relationships for Organophosphates Binding to Trypsin and Chymotrypsin.
2010. Wright State University, Master's thesis.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=wright1278010674.
MLA Style (8th edition)
Ruark, Christopher. "Quantitative Structure-Activity Relationships for Organophosphates Binding to Trypsin and Chymotrypsin." Master's thesis, Wright State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=wright1278010674
Chicago Manual of Style (17th edition)
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Document number:
wright1278010674
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Copyright Info
© 2010, all rights reserved.
This open access ETD is published by Wright State University and OhioLINK.