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Structure and Mode of Action of Organophosphate Pesticides:

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Presentation on theme: "Structure and Mode of Action of Organophosphate Pesticides:"— Presentation transcript:

1 Structure and Mode of Action of Organophosphate Pesticides:
A Computational Study Lasantha Rathnayake Scott H. Northrup Department of Chemistry Tennessee Technological University

2 Organophosphate (OP) compounds
An important class of man-made chemicals actively released into the environment is the organophosphates Dichlorvos

3 Applications of OP compounds
Pesticides Parathion, paraoxon, and diazinon Chemical warfare agents Sarin, soman, tabun, and VX Therapeutic agents Echothiophate iodide to treat glaucoma

4 Applications of OP Compounds
Presence of OP-containing pesticides in the environment is abundant. Pesticide exposure arises from living next to treated areas or in agricultural regions, as well as from house and yard pesticide treatment.

5 Pesticide transportation paths to organism
Pesticide transportation paths to untargeted organism World Health Organization (WHO), 2001

6 Main action of OPs as pesticides
Inhibit the activity of the enzyme acetylcholinesterase (AcHE) which is hydrolase of the neurotransmitter acetylcholine (ACh) in the nervous system (central and peripheral nervous system) Mouse AcHE Human AcHE mAcHE: Carletti et. al., Journal of the American Chemical Society, 2008 hAcHE: Carletti et. al., Journal of medicinal chemistry, 2010

7 Action of OPs with serine
Phosphorylation dealkylation and hydroxylation mechanisms of OPs with serine at active site of AcHE Elersek and Filipic, InTech, 2011

8 Tabun (an OP) with mouse AcHE
Crystal structures of mouse AcHE with covalently bonded tabun: nonaged (left) and aged (right) Carletti et. al., Journal of the American Chemical Society, 2008

9 Remarks Although a basic understanding exists as to how these compounds function and their toxicological effects, much remains to be understood about how details of their molecular structure relate to toxicity and species specificity. What makes one OP a good candidate for a household insecticide while another OP is a chemical warfare agent? What structural features give rise to specificity for toxicity in different organisms? What are the fates of these compounds in the environment? Are there ways to more effectively remediate or reverse their detrimental effects on organisms in the environment?

10 Remarks Better understanding of the thermodynamics/kinetics of the reactions of OPs could lead to following Design superior pesticides with greater margins of safety. Development of preventative strategies for bodily exposure to chemical warfare agents. Reversal of detrimental effects of exposure of OPs to humans and the environment.

11 Project Goals Explore the equilibrium structures and reactivities of ten OPs widely used as pesticides. Perform conformational analyses of the compounds to determine most stable conformations. Explore pathways of reaction of OPs with nucleophiles mimicking their target enzyme AcHE. Use advanced knowledge-based ligand docking algorithms available in the software Rosetta to predict the docking of OPs to AChE and subsequent pathways for binding. Rosetta : Kaufmann et. al., Biochemistry, 2010

12 Computational Methodologies
Gaussian 03 Hybrid density functional theory (HDFT) method of mPW1B95-44 in conjunction with G(d,p) basis set. Reaction paths Conformations Rosetta Obtain and analyze docking poses QSAR

13 Some of the conformations of OPs in consideration
Atom colors C - dark green O - red Cl - light green N - blue H - gray S - yellow P - orange Toxicity – Category I and II Low molecular weight Currently in use Variety of functional groups

14 Reaction of OP with methanol:
Direct H transfer Methanol mimics the activity of serine residue in active site of AcHE ΔE≠ = (kcal/mol) Pre complex Transition state H transfer from methanol to leaving group of dichlorovos

15 Reaction of OP with methanol: Multi step Wright mechanism
Wright and White, J. Molecular Structure (Theochem), 1998

16 Reaction of OP with methanol: Water assisted Wright mechanism

17 Direct vs water assisted Wright mechanisms
Purple – direct Wright mechanism Blue –water assisted mechanism

18 Work in progress Histidine assisted H – transfer

19 Work in progress Docking using Rosetta and analyzing the outcomes
Dichlorovos in hAcHE

20 Work in progress Docking using Rosetta and analyzing the outcomes
Dichlorovos in hAcHE

21 Current conclusions Reactivity of OPs with methanol, which mimics AChE, was studied in different perspectives. Wright mechanism shows substantially lower activation energies than the direct mechanism. However, values are still high. Water-assisted Wright mechanism dramatically lowers the activation energies suggesting a biologically feasible reaction path for the reaction of OPs and AChE.

22 References Aprea, C.; Strambi, M.; Novelli, M.T.; Lunghini, L. & Bozzi, N. Biologic monitoring of exposure to organophosphorus pesticides in 195 Italian children. Environ Health Perspect 108 (6): 2000,   Barr, D.B.; Bravo, R.; Weerasekera, G.; Caltabiano, L.M.; Whitehead, R.D. Jr.; Olsson, A.O.; Caudill, S.P.; Schober, S.E.; Pirkle, J.L. & Sampson, E.J. Concentrations of dialkyl phosphate metabolites of organophosphorus pesticides in the U.S. population. Environ Health Perspect 112 (2):2004,   Berman, H. M., et al (2002) The Protein Data Bank. Acta Crystallogr. D58, 899–907. Bernstein, F. C., Koetzle, T. F., Williams, G. J., Meyer, E. F., Jr., Brice, M. D., Rodgers, J. R., Kennard, O., Shimanouchi, T., and Tasumi, M. (1977) The Protein Data Bank: A computer-based archival file for macromolecular structures. J. Mol. Biol. 112, 535–542. Bock, C.W., Larkin, J.D., Hirsch, S.S., Wright, J.B., Nucleophilic destruction of organophosphate toxins: A computational investigation, Journal of Molecular Structure: THEOCHEM 915 (2009) 11–19. Britt, J. K. Properties and Effects of Pesticides. Principles of Toxicology: Environmental and Industrial Applications, 2nd ed; Williams, P. L.; James, R. C. and Roberts, S. M., Ed,; John Wiley & Sons, Inc, New York, 2000; pp Casida, John E.; Quistad, Gary B, Why insecticides are more toxic to insects than people: the unique toxicology of insects, Journal of Pesticide Science (Tokyo, Japan) (2004), 29(2), 81-86. Carletti, E.; Colletier, J. P; Dupeux, F.; Trovaslet, M.; Masson, P. and Nachon F. Structural evidence that human acetylcholinesterase inhibited by tabun ages through O-dealkylation., J Med Chem., 2010, 27;53(10), Carletti, E., Colletier, J. P., Dupeux, F., Trovaslet, M., Masson, P., & Nachon, F. (2010). Structural evidence that human acetylcholinesterase inhibited by tabun ages through O-dealkylation. Journal of medicinal chemistry, 53(10), Carletti, E., Li, H., Li, B., Ekström, F., Nicolet, Y., Loiodice, M., ... & Nachon, F. (2008). Aging of cholinesterases phosphylated by tabun proceeds through O-dealkylation. Journal of the American Chemical Society, 130(47),  Curl, C.L.; Fenske, R.A. & Elgethun, K. Organophosphorus pesticide exposure of urban and suburban preschool children with organic and conventional diets. Environ Health Perspect 111 (3): 2003, Ekstrom, F., Akfur, C. Tunemalm, A-K, Lundberg, S., Structural Changes of Phenylalanine 338 and Histidine 447 Revealed by the Crystal Structures of Tabun-Inhibited Murine Acetylcholinesterase, Biochemistry 2006, 45, 74-81 Elersek, T. and Filipic, M, Organophosphorous Pesticides - Mechanisms of Their Toxicity, Pesticides - The Impacts of Pesticides Exposure, Stoytcheva, M. (Ed.), InTech, 2011. Gunnell, D., and Eddleston, M. (2003) Suicide by intentional ingestion of pesticides: a continuing tragedy in developing countries, Int. J. Epidemiol. 32, Gupta, R.C., Toxicology of Organophosphate & Carbamate Compounds, Acad. Press, 2006. Hodgson, E., “A textbook of modern toxicology, ” Wiley & Sons, Inc., New Jersey, 3rd ed., 2004. Kaufmann, K. W., Lemmon, G. H., DeLuca, S. L., Sheehan, J. H., & Meiler, J. (2010). Practically useful: what the Rosetta protein modeling suite can do for you. Biochemistry, 49(14), Kwong, T. C. (2002) Organophosphate pesticides: biochemistry and clinical toxicology, Ther. Drug Monit. 24, Marciano, D.; Columbus, I.; Elias, S.; Goldvaser, M.; Shoshanim, O.; Ashkenazi, N. and Zafrani, Y. Role of the P−F Bond in Fluoride-Promoted Aqueous VX Hydrolysis: An Experimental and Theoretical Study., J. Org. Chem. 2012, 77, 10042−10049.  Mileson, B. E.; Chambers, J. E.; Chen, W. L.; Dettbarn, W.; Ehrich, M.; Eldefrawi, A. T.; Gaylor, D. W.; Hamernik, K.; Hodgson, E.; Karczmar, A. G.; Padilla, S.; Pope, C. N.; Richardson, R. J.; Saunders, D. R.; Sheets, L. P.; Sultatos, L. G.; Wallace, K. B. Common mechanism of toxicity: a case study of organophosphorus pesticides. Toxicol. Sci. 1998, 41, 8−20. Sanson, B.; Nachon, F; Colletier, J. P.; Froment, M. T.; Toker, L.; Greenblatt, H. M.; Sussman, J. L.; Ashani, Y.; Masson, P.; Silman, I. and Weik, M. Crystallographic Snapshots of Nonaged and Aged Conjugates of Soman with Acetylcholinesterase, and of a Ternary Complex of the Aged Conjugate with Pralidoxime., Journal of Medicinal Chemistry, 2009, 52 (23),  US EPA Precautionary Statements Label Review Manual, Chapter 7: 2012 revision.  WHO Organophosphorous pesticides in the environment- Integrated Risk Assessment, Geneva: WHO 2001.  Wright, J.B. and White, W.E., J. Molecular Structure (Theochem) 454 (1998)


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