Skip to main content
SpringerLink
Log in

A mechanism-based 3D-QSAR approach for classification and prediction of acetylcholinesterase inhibitory potency of organophosphate and carbamate analogs

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Organophosphate (OP) and carbamate esters can inhibit acetylcholinesterase (AChE) by binding covalently to a serine residue in the enzyme active site, and their inhibitory potency depends largely on affinity for the enzyme and the reactivity of the ester. Despite this understanding, there has been no mechanism-based in silico approach for classification and prediction of the inhibitory potency of ether OPs or carbamates. This prompted us to develop a three dimensional prediction framework for OPs, carbamates, and their analogs. Inhibitory structures of a compound that can form the covalent bond were identified through analysis of docked conformations of the compound and its metabolites. Inhibitory potencies of the selected structures were then predicted using a previously developed three dimensional quantitative structure-active relationship. This approach was validated with a large number of structurally diverse OP and carbamate compounds encompassing widely used insecticides and structural analogs including OP flame retardants and thio- and dithiocarbamate pesticides. The modeling revealed that: (1) in addition to classical OP metabolic activation, the toxicity of carbamate compounds can be dependent on biotransformation, (2) OP and carbamate analogs such as OP flame retardants and thiocarbamate herbicides can act as AChEI, (3) hydrogen bonds at the oxyanion hole is critical for AChE inhibition through the covalent bond, and (4) π–π interaction with Trp86 is necessary for strong inhibition of AChE. Our combined computation approach provided detailed understanding of the mechanism of action of OP and carbamate compounds and may be useful for screening a diversity of chemical structures for AChE inhibitory potency.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Čolović MB, Krstić DZ, Lazarević-Paši TD, Bondžić AM, Vasić VM (2013) Acetylcholinesterase Inhibitors: pharmacology and toxicology. Curr Neuropharmacol 11:315–335

    Article  Google Scholar 

  2. Sussman JL, Harel M, Frolow F, Varon L, Toker L, Futerman AH, Silman I (1988) Purification and crystallization of a dimeric form of acetylcholinesterase from Torpedo californica subsequent to solubilization with phosphatidylinositol-specific phospholipase C. J Mol Biol 203:821–823

    Article  CAS  Google Scholar 

  3. Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, Silman I (2002) Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine. Biochemistry 41:3555–3564

    Article  CAS  Google Scholar 

  4. Rydberg EH, Brumshtein B, Greenblatt HM, Wong DM, Shaya D, Williams LD, Carlier PR, Pang YP, Silman I, Sussman JL (2006) Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge. J Med Chem 49:5491–5500

    Article  CAS  Google Scholar 

  5. Carletti E, Colletier JP, Schopfer LM, Santoni G, Masson P, Lockridge O, Nachon F, Weik M (2013) Inhibition pathways of the potent organophosphate CBDP with cholinesterases revealed by X-ray crystallographic snapshots and mass spectrometry. Chem Res Toxicol 26:280–289

    Article  CAS  Google Scholar 

  6. Ordentlich A, Barak D, Kronman C, Ariel N, Segall Y, Velan B, Shafferman A (1996) The architecture of human acetylcholinesterase active center probed by interactions with selected organophosphate inhibitors. J Biol Chem 271:11953–11962

    Article  CAS  Google Scholar 

  7. Ordentlich A, Barak D, Kronman C, Ariel N, Segall Y, Velan B, Shafferman A (1998) Functional characteristics of the oxyanion hole in human acetylcholinesterase. J Biol Chem 273:19509–19517

    Article  CAS  Google Scholar 

  8. Fukuto TR (1990) Mechanism of action of organophosphorus and carbamate insecticides. Environ Health Perspect 87:245–254

    Article  CAS  Google Scholar 

  9. Gibson GG, Skett P (1994) Introduction to drug metabolism, 2nd edn. Blackie, London

    Google Scholar 

  10. Lee S, Kang YM, Park H, Dong MS, Shin JM, No KT (2013) Human nephrotoxicity prediction models for three types of kidney injury based on data sets of pharmacological compounds and their metabolites. Chem Res Toxicol 26:1652–1659

    Article  CAS  Google Scholar 

  11. Yazal JE, Rao SN, Mehl A, Slikker W Jr (2001) Prediction of organophosphorus acetylcholinesterase inhibition using three-dimensional quantitative structure-activity relationship (3D-QSAR) methods. Toxicol Sci 63:223–232

    Article  Google Scholar 

  12. Chaudhaery SS, Roy KK, Shakya N, Saxena G, Sammi SR, Nazir A, Nath C, Saxena AK (2010) Novel carbamates as orally active acetylcholinesterase inhibitors found to improve scopolamine-induced cognition impairment: pharmacophore-based virtual screening, synthesis, and pharmacology. J Med Chem 53:6490–6505

    Article  CAS  Google Scholar 

  13. Vitorović-Todorović MD, Cvijetić IN, Juranić IO, Drakulić BJ (2012) The 3D-QSAR study of 110 diverse, dual binding, acetylcholinesterase inhibitors based on alignment independent descriptors (GRIND-2). The effects of conformation on predictive power and interpretability of the models. J Mol Graph Model 38:194–210

    Article  Google Scholar 

  14. Wong KY, Mercader AG, Saavedra LM, Honarparvar B, Romanelli GP, Duchowicz PR (2014) QSAR analysis on tacrine-related acetylcholinesterase inhibitors. J Biomed Sci 20:21–84

    Google Scholar 

  15. Deb PK, Sharma A, Piplani P, Akkinepally RR (2012) Molecular docking and receptor-specific 3D-QSAR studies of acetylcholinesterase inhibitors. Mol Divers 16:803–823

    Article  CAS  Google Scholar 

  16. Lee S, Barron MG (2015) Development of 3D-QSAR model for acetylcholinesterase inhibitors using a combination of fingerprint, molecular docking, and structure-based pharmacophore approaches. Toxicol Sci 148:60–70

    Article  CAS  Google Scholar 

  17. Barron MG, Lilavois CR, Martin TM (2015) MOAtox: a comprehensive mode of action and acute aquatic toxicity database for predictive model development. Aquat Toxicol 161:102–107

    Article  CAS  Google Scholar 

  18. Wishart D, Arndt D, Pon A, Sajed T, Guo AC, Djoumbou Y, Knox C, Wilson M, Liang Y, Grant J, Liu Y, Goldansaz SA, Rappaport SM (2015) T3DB: the toxic exposome database. Nucleic Acids Res 43:D928–D934

    Article  Google Scholar 

  19. Wei GL, Li DQ, Zhuo MN, Liao YS, Xie ZY, Guo TL, Li JJ, Zhang SY, Liang ZQ (2015) Organophosphorus flame retardants and plasticizers: sources, occurrence, toxicity and human exposure. Environ Pollut 196:29–46

    Article  CAS  Google Scholar 

  20. Fest C, Schmidt KJ (1982) The chemistry of organophosphorus pesticides, 2nd edn. Springer, Berlin

    Book  Google Scholar 

  21. Fernandes LS, Emerick GL, dos Santos NA, de Paula ES, Barbosa F Jr, dos Santos AC (2015) In vitro study of the neuropathic potential of the organophosphorus compounds trichlorfon and acephate. Toxicol In Vitro 29:522–528

    Article  CAS  Google Scholar 

  22. Pesticide Residues in Food (2005) Report of the joint meeting of the FAO panel of experts on pesticide residues in food and the environment and the WHO core assessment group on pesticide residues. Geneva, Switzerland, 20–29 Sept 2005

  23. Mdegela RH, Mosha RD, Sandvik M, Skaare JU (2010) Assessment of acetylcholinesterase activity in Clarias gariepinus as a biomarker of organophosphate and carbamate exposure. Ecotoxicology 19:855–863

    Article  CAS  Google Scholar 

  24. Ma M, Zhang B, Li SC (2011) Purification and partial characterization of acetlcholinesterase from Pardosa astrigera L. Koch. J Cell Anim Biol 5:11–16

    Google Scholar 

  25. Williamson SM, Moffat C, Gomersall MA, Saranzewa N, Connolly CN, Wright GA (2013) Exposure to acetylcholinesterase inhibitors alters the physiology and motor function of honeybees. Front Physiol 4:13

    Article  Google Scholar 

  26. Čolovića MB, Krstićb DZ, Ušćumlićc GS, Vasić VM (2011) Single and simultaneous exposure of acetylcholinesterase to diazinon, chlorpyrifos and their photodegradation products. Pestic Biochem Physiol 100:16–22

    Article  Google Scholar 

  27. Sogorb MA, González-González I, Pamies D, Vilanova E (2010) An alternative in vitro method for detecting neuropathic compounds based on acetylcholinesterase inhibition and on inhibition and aging of neuropathy target esterase (NTE). Toxicol In Vitro 24:942–952

    Article  CAS  Google Scholar 

  28. Mortensen SR, Hooper MJ, Padilla S (1998) Rat brain acetylcholinesterase activity: developmental profile and maturational sensitivity to carbamate and organophosphorus inhibitors. Toxicology 125:13–19

    Article  CAS  Google Scholar 

  29. Guo X, Zhang X, Cai Q, Shen T, Zhu S (2013) Developing a novel sensitive visual screening card for rapid detection of pesticide residues in food. Food Control 30:15–23

    Article  CAS  Google Scholar 

  30. Ehrich M, Correll L, Veronesi B (1997) Acetylcholinesterase and neuropathy target esterase inhibitions in neuroblastoma cells to distinguish organophosphorus compounds causing acute and delayed neurotoxicity. Fund Appl Toxicol 38:55–63

    Article  CAS  Google Scholar 

  31. Swale DR, Tong F, Temeyer KB, Li A, Lam PC, Totrov MM, Carlier PR, Pérez de León AA, Bloomquist JR (2013) Inhibitor profile of bis(n)-tacrines and N-methylcarbamates on acetylcholinesterase from Rhipicephalus (Boophilus) microplus and Phlebotomus papatasi. Pestic Biochem Physiol 106:85–92

    Article  CAS  Google Scholar 

  32. Chuiko GM (2000) Comparative study of acetylcholinesterase and butyrylcholinesterase in brain and serum of several freshwater fish: specific activities and in vitro inhibition by DDVP, an organophosphorus pesticide. Comp Biochem Physiol 127:233–242

    CAS  Google Scholar 

  33. Kasagami T, Miyamoto T, Yamamoto I (2002) Activated transformations of organophosphorus insecticides in the case of non-AChE inhibitory oxons. Pest Manag Sci 58:1107–1117

    Article  CAS  Google Scholar 

  34. Wang C, Murphy SD (1982) Kinetic analysis of species difference in acetylcholinesterase sensitivity to organophosphate insecticides. Toxicol Appl Pharmacol 66:409–419

    Article  CAS  Google Scholar 

  35. Yen JH, Tsai CC, Wang YS (2003) Separation and toxicity of enantiomers of organophosphorus insecticide leptophos. Ecotoxicol Environ Saf 55:236–242

    Article  CAS  Google Scholar 

  36. Oujji NB, Bakas I, Istamboulié G, Ait-Ichou I, Ait-Addi E, Rouillon R, Noguer T (2012) Acetylcholinesterase immobilized on magnetic beads for pesticides detection: application to olive oil analysis. Sensors 12:7893–7904

    Article  Google Scholar 

  37. Oujji NB, Bakas I, Istamboulié G, Ait-Ichou I, Ait-Addi E, Rouillon R, Noguer T (2014) An easy-to-use colorimetric enzymatic test-system for organophosphorus insecticides detection in olive oil. Sci Innov 2:5–9

    Google Scholar 

  38. Milatovic D, Dettbarn WD (1996) Modification of acetylcholinesterase during adaptation to chronic, subacute paraoxon application in rat. Toxicol Appl Pharmacol 136:20–28

    Article  CAS  Google Scholar 

  39. Pohanka M, Binder J, Kuca K (2009) Sarin assay using acetylcholinesterases and electrochemical sensor strip. Defence Sci J 59:300–304

    Article  CAS  Google Scholar 

  40. Dong JX, Xie X, He YS, Beier RC, Sun YM, Xu ZL, Wu WJ, Shen YD, Xiao ZL, Lai LN, Wang H, Yang JY (2013) Surface display and bioactivity of Bombyx mori acetylcholinesterase on Pichia pastoris. PLoS ONE 8:e70451

    Article  CAS  Google Scholar 

  41. Anguiano GA, Amador A, Moreno-Legorreta M, Arcos-Ortega F, Vazquez-Boucard C (2010) Effects of exposure to oxamyl, carbofuran, dichlorvos, and lindane on acetylcholinesterase activity in the gills of the Pacific oyster Crassostrea gigas. Environ Toxicol 25:327–332

    Article  CAS  Google Scholar 

  42. Bracha P, O’Brien RD (1968) Trialkyl phosphate and phosphorothiolate anticholinesterases. II. Effects of chain length on potency. Biochemistry 7:1555–1559

    Article  CAS  Google Scholar 

  43. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comp Chem 31:455–461

    CAS  Google Scholar 

  44. Molecular Operating Environment (MOE) (2015) Chemical Computing Group Inc., Montreal

  45. Sanner MF (1999) Python: a programming language for software integration and development. J Mol Graphics Mod 17:57–61

    CAS  Google Scholar 

  46. Huang SY, Zou X (2007) Ensemble docking of multiple protein structures: considering protein structural variations in molecular docking. Proteins 66:399–421

    Article  CAS  Google Scholar 

  47. Zhang Y, Kua J, McCammon JA (2002) Role of the catalytic triad and oxyanion hole in acetylcholinesterase catalysis: an ab initio QM/MM study. J Am Chem Soc 124:10572–10577

    Article  CAS  Google Scholar 

  48. Schowen KB, Limbach HH, Denisov GS, Schowen RL (2000) Hydrogen bonds and proton transfer in general-catalytic transition-state stabilization in enzyme catalysis. Biochim Biophys Acta 1458:43–62

    Article  CAS  Google Scholar 

  49. Saxena A, Redman AM, Jiang X, Lockridge O, Doctor BP (1997) Differences in active site gorge dimensions of cholinesterases revealed by binding of inhibitors to human butyrylcholinesterase. Biochemistry 36:14642–14651

    Article  CAS  Google Scholar 

  50. Groner E, Ashani Y, Schorer-Apelbaum D, Sterling J, Herzig Y, Weinstock M (2007) The kinetics of inhibition of human acetylcholinesterase and butyrylcholinesterase by two series of novel carbamates. Mol Pharmacol 71:1610–1617

    Article  CAS  Google Scholar 

  51. Mahajna M, Quistad GB, Casida JE (1997) Acephate insecticide toxicity: safety conferred by inhibition of the bioactivating carboxyamidase by the metabolite methamidophos. Chem Res Toxicol 10:64–69

    Article  CAS  Google Scholar 

  52. Eto M, Casida JE, Eto T (1962) Hydroxylation and cyclization reactions involved in the metabolism of tri-o-cresyl phosphate. Biochem Pharmacol 11:337–352

    Article  CAS  Google Scholar 

  53. Hoffman K, Garantziotis S, Birnbaum LS, Stapleton HM (2015) Monitoring indoor exposure to organophosphate flame retardants: hand wipes and house dust. Environ Health Perspect 123:160–165

    Google Scholar 

  54. Kanchi S, Singh P, Bisetty K (2014) Dithiocarbamates as hazardous remediation agent: a critical review on progress in environmental chemistry for inorganic species studies of 20th century. Arabian J Chem 7:11–25

    Article  CAS  Google Scholar 

  55. Mathieu C, Duval R, Xu X, Rodrigues-Lima F, Dupret JM (2015) Effects of pesticide chemicals on the activity of metabolic enzymes: focus on thiocarbamates. Expert Opin Drug Metab Toxicol 11:81–94

    CAS  Google Scholar 

  56. Nomeir AA, Abou-Donia MB (1986) Studies on the metabolism of the neurotoxic tri-o-cresyl phosphate. Distribution, excretion, and metabolism in male cats after a single, dermal application. Toxicology 38:15–33

    Article  CAS  Google Scholar 

  57. Gosselin RE, Smith RP, Hodge HC (1984) Clinical toxicology of commercial products, 5th edn. Williams and Wilkens, Baltimore

    Google Scholar 

  58. National Toxicology Program (NTP) (1991) Toxicology and carcinogenesis studies of tris(2-chloroethyl) phosphate (CAS No. 115-96-8) in F344/N rats and B6C3F1 mice (Gavage Studies). Natl Toxicol Program Tech Rep 391:1–233

    Google Scholar 

  59. U.S. EPA (2001) Thiocarbamate: a determination of the existence of a common mechanism of toxicity and a screening level cumulative food risk assessment. Washington, DC, U.S. Environmental Protection Agency

    Google Scholar 

  60. Fernández-Vega C, Sancho E, Ferrando MD, Andreu-Moliner E (1999) Thiobencarb toxicity and plasma AChE inhibition in the European eel. J Environ Sci Health B 34:61–73

    Article  Google Scholar 

  61. Sancho E, Fernandez-Vega C, Sanchez M, Ferrando MD, Andreu-Moliner E (2000) Alterations on AChE activity of the fish Anguilla anguilla as response to herbicide-contaminated water. Ecotoxicol Environ Saf 46:57–63

    Article  CAS  Google Scholar 

  62. Russom CL, LaLone CA, Villeneuve DL, Ankley GT (2014) Development of an adverse outcome pathway for acetylcholinesterase inhibition leading to acute mortality. Environ Toxicol Chem 33:2157–2169

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported in part by an appointment to the ORISE participant research program supported by an interagency agreement between the U.S. EPA and the U.S. Department of Energy. We thank Carlie LaLone for review of a draft of the manuscript. The conclusions may not necessarily reflect the views of EPA and no official endorsement should be inferred.

Author information

Authors and Affiliations

  1. Gulf Ecology Division, U.S. Environmental Protection Agency, Gulf Breeze, FL, 32561, USA

    Sehan Lee & Mace G. Barron

Authors
  1. Sehan Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mace G. Barron
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sehan Lee.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, S., Barron, M.G. A mechanism-based 3D-QSAR approach for classification and prediction of acetylcholinesterase inhibitory potency of organophosphate and carbamate analogs. J Comput Aided Mol Des 30, 347–363 (2016). https://doi.org/10.1007/s10822-016-9910-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-016-9910-7

Keywords

Search

Navigation