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Pertanika Journal of Science & Technology

Official journal of Universiti Putra Malaysia for scholarly work across science, engineering and related technologies.

e-ISSN 2231-8526 ISSN 0128-7680
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Research article

In silico Study of Potential Non-oxime Reactivator for Sarin-inhibited Human Acetylcholinesterase

Rauda A. Mohamed, Keat Khim Ong, Norhana Abdul Halim, Noor Azilah Mohd Kasim, Siti Aminah Mohd Noor, Victor Feizal Knight, Rabbani Muhamad and Wan Md Zin Wan Yunus

Volume 29, Issue 3 July 2021 Published 31 July 2021
https://doi.org/10.47836/pjst.29.3.19
KeywordsAntidote, docking, in silico, inhibition, organophosphate, oxime, reactivator, simulation
Article content

Abstract

The search for new compounds other than oxime as potential reactivator that is effective upon organophosphate poisoning treatments is desired. The less efficacy of oxime treatment has been the core factor. Fourteen compounds have been screened via in silico approach for their potential as sarin-inhibited human acetylcholinesterase poisoning antidotes. The selection of the compounds to be synthesized based on this computational screening, reduces the time and cost needed. To perform the docking study of sarin-inhibited acetylcholinesterase and reactivator-sarin inhibited acetylcholinesterase complexations, a bioinformatics tool was used. Estimation of the nucleophilic attack distance and binding energy of fourteen potential compounds with sarin inhibited acetylcholinesterase complexes to determine their antidote capacities was carried out using Autodock. A commercially available antidote, 2-PAM was used for the comparison. The best docked-pose was further examined with molecular dynamics simulation. Apart from being lipophilic, a compound with a carboxylic acid, (R)-Boc-nipecotic acid is shown to exhibit 6.29 kcal/mol binding energy with 8.778 Å distance of nucleophilic attack. The stability and flexibility of the sarin-inhibited acetylcholinesterase, complexed with (R)-Boc-nipecotic acid suggests this compound should be tested experimentally as a new, promising antidote for sarin-inhibited acetylcholinesterase poisoning.
Supporting literature

References

  1. Abou-Donia, M. B., Siracuse, B., Gupta, N., & Sokol, A. S. (2016). Sarin (GB, O isopropyl methylphosphonofluoridate) neurotoxicity: Critical review. Critical Reviews in Toxicology, 46(10), 845-875. https://doi.org/10.1080/10408444.2016.1220916
  2. Ajami, D., & Rebek, J. (2013). Chemical approaches for detection and destruction of nerve agents. Organic and Biomolecular Chemistry, 11(24), 3936-3942. https://doi.org/10.1039/c3ob40324f
  3. Artursson, E., Akfur, C., Hornberg, A., Worek, F., & Ekstrom, F. (2009). Reactivation of tabun-hAChE investigated by structurally analogous oximes and mutagenesis. Toxicology, 265(3), 108-114. https://doi.org/10.1016/j.tox.2009.09.002
  4. Bagaria, A., Jaravine, V., Huang, Y. J., Montelione, G. T., & Guntert, P. (2012). Protein structure validation by generalized linear model root-mean-square deviation prediction. Protein Science, 21(2), 229-238. https://doi.org/10.1002/pro.2007
  5. Baker, S. R. (1990). The effects of pesticides on human health. In C. F. Wilkinson (Ed.), Advances in modern environmental toxicology (pp. 35-130). Princeton Scientific Publication.
  6. Barak, D., Kronman, C., Ordentlich, A., Ariel, N., Bromberg, A., Marcus, D., Lazara, A., Velan, B., & Shafferman, A. (1994). Acetylcholinesterase peripheral anionic site degeneracy conferred by amino acid arrays sharing a common core. Journal of Biological Chemistry, 269(9), 6296-6305. https://doi.org/10.1016/S0021-9258(17)37371-4
  7. Baweja, M., Singh, P. K., Sadaf, A., Tiwari, R., Nain, L., Khare, S. K., & Shukla, P. (2017). Cost effective characterization process and molecular dynamic simulation of detergent compatible alkaline protease from Bacillus pumilus strain MP27. Process Biochemistry, 58, 199-203. https://doi.org/10.1016/j.procbio.2017.04.024
  8. Bhattacharjee, A. K., Marek, E., Le, H. T., Ratcliffe, R., DeMar, J. C., Pervitsky, D., & Gordon, R. K. (2015). Discovery of non-oxime reactivators using an in silico pharmacophore model of reactivators for DFP-inhibited acetylcholinesterase. European Journal of Medicinal Chemistry, 90, 209-220. https://doi.org/10.1016/j.ejmech.2014.11.013
  9. Brighente, I. M. C., & Yunes, R. A. (1997). The general mechanisms of attack of nitrogen nucleophiles on carbonyl compounds. Facts that determine the change of the rate-pH profiles. Journal of the Brazillian Chemical Society, 8(5), 549-553. d https://doi.org/10.1590/S0103-50531997000500018
  10. Cadieux, C. L., Wang, H., Zhang, Y., Koenig, J. A., Shih, T. M., McDonough, J., Koh, J., & Cerasoli, D. (2016). Probing the activity of a non-oxime reactivator for acetylcholinesterase inhibited by organophosphorus nerve agents. Chemico-Biological Interactions, 259(Pt B), 133-141. https://doi.org/10.1016/j.cbi.2016.04.002
  11. Chen, D. E., Willick, D. L., Ruckel, J. B., & Floriano, W. B. (2015). Principal component analysis of binding energies for single-point mutants of hT2R16 bound to an agonist correlate with experimental mutant cell response. Journal of Computational Biology, 22(1), 37-53. https://doi.org/10.1089/cmb.2014.0192
  12. Colovic, M. B., Krstic, D. Z., Lazarevic-Pasti, T. D., Bondzic, A. M., & Vasic, V. M. (2013). Acetylcholinesterase inhibitors: Pharmacology and toxicology. Current Neuropharmacology, 11(3), 315-335. https://doi.org/10.2174/1570159x11311030006
  13. de Almeida, J. S. F. D., Guizado, T. R. C., Guimarães, A. P., Ramalho, T. C., Gonçalves, A. S., de Koning, M. C., & França, T. C. C. (2016). Docking and molecular dynamics studies of peripheral site ligand–oximes as reactivators of sarin-inhibited human acetylcholinesterase. Journal of Biomolecular Structure and Dynamics, 34(12), 1-11. https://doi.org/10.1080/07391102.2015.1124807
  14. de Koning, M. C., Horn, G., Worek, F., & Grol, M. V. (2018). Discovery of a potent non-oxime reactivator of nerve agent inhibited human acetylcholinesterase. European Journal of Medicinal Chemistry, 157, 151-160. https://doi.org/10.1016/j.ejmech.2018.08.016
  15. de Koning, M. C., Joosen, M. J. A., Worek, F., Nachon, F., van Grol, M., Klaassen, S. D., Alkema, D. P. W., Wille, T., & de Bruijn, H. M. (2017). Application of the Ugi multicomponent reaction in the synthesis of reactivators of nerve agent inhibited Acetylcholinesterase. Journal of Medicinal Chemistry, 60(22), 9376-9392. https://doi.org/10.1021/acs.jmedchem.7b01083
  16. de Koning, M. C., van Grol, M., & Noort, D. (2011). Peripheral site ligand conjugation to a non-quaternary oxime enhances reactivation of nerve agent-inhibited human acetylcholinesterase. Toxicology Letters, 206(1), 54-59. https://doi.org/10.1016/j.toxlet.2011.04.004
  17. de Souza, F. R., Garcia, D. R., Cuya, T., Pimentel, A. S., Gonçalves, A. S., de Alencastro, R. B., & França, T. C. C. (2020). Molecular modeling study of uncharged oximes compared to HI-6 and 2-PAM inside human AChE sarin and VX conjugates. American Chemical Society Omega, 5(9), 4490-4500. https://doi.org/10.1021/acsomega.9b03737
  18. Duan, Y., Wu, C., Chowdhury, S., Lee, M. C., Xiong, G., Zhang, W., Yang, R., Cieplak, P., Luo, R., Lee, T., Caldwell, J., Wang, J., & Kollman, P. (2003). A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. Journal of Computational Chemistry, 24(16), 1999-2012. https://doi.org/10.1002/jcc.10349
  19. Ishak, S. N. H., Aris, S. N. A. M., Halim, K. B. A., Ali, M. S. M., Leow, T. C., Kamarudin, N. H. A., Masomian, M., & Rahman, R. N. Z. R. A. (2017). Molecular dynamic simulation of space and earth-grown crystal structures of thermostable T1 lipase Geobacillus zalihae revealed a better structure. Molecules, 22(10), Article 1574. https://doi.org/10.3390/molecules22101574
  20. Johnson, G., & Moore, S. (2006). The peripheral anionic site of acetylcholinesterase: structure, functions and potential role in rational drug design. Current Pharmaceutical Design, 12(2), 217-225. https://doi.org/10.2174/138161206775193127
  21. Katz, F. S., Pecic, S., Schneider, L., Zhu, Z., Hastings-Robinson, A., Luzac, M., Macdonald, J., Landry, D. W., & Stojanovic, M. N. (2018). New therapeutic approaches and novel alternatives for organophosphate toxicity. Toxicology Letters, 291, 1-10. https://doi.org/10.1016/j.toxlet.2018.03.028
  22. Katz, F. S., Pecic, S., Tran, T. H., Trakht, I., Schneider, L., Zhu, Z., Ton-That, L., Luzac, M., Zlatanic, V., Damera, S., Macdonald, J., Landry, D. W., Tong, L., & Stojanovic, M. N. (2015). Discovery of new classes of compounds that reactivate acetylcholinesterase inhibited by organophosphates. ChemBioChem, 16(15), 2205-2215. https://doi.org/10.1002/cbic.201500348
  23. Kim, S., Thiessen, P. A., Bolton, E. E., Chen, J., Fu, G., Gindulyte, A., Han, L., He, J., He, S., Shoemaker, B. A., Wang, J., Yu, B., Zhang, J., & Bryant, S. H. (2016). PubChem substance and compound databases. Nucleic Acids Research, 44(D1), D1202-D1213. https://doi.org/10.1093/nar/gkv951
  24. Konagurthu, A. S., Whisstock, J. C., Stuckey, P. J., & Lesk, A. M. (2006). MUSTANG: A multiple structural alignment algorithm. Proteins: Structure, Function, and Bioinformatics, 64(3), 559-574. https://doi.org/10.1002/prot.20921
  25. Kovarik, Z., MačEk, N., Sit, R. K., Radić, Z., Fokin, V. V., Sharpless, K., & Taylor, P. (2013). Centrally acting oximes in reactivation of tabun-phosphoramidated AChE. Chemico-Biological Interactions, 203(1), 77-80. https://doi.org/10.1016/j.cbi.2012.08.019
  26. Krieger, E., Koraimann, G., & Vriend, G. (2002). Increasing the precision of comparative models with YASARA NOVA—A self-parameterizing force field. Proteins, 47(3), 393-402. https://doi.org/10.1002/prot.10104
  27. Krieger, E., & Vriend, G. (2014). YASARA View - molecular graphics for all devices - from smartphones to workstations. Bioinformatics, 30(20), 2981-2982. https://doi.org/10.1093/bioinformatics/btu426
  28. Kryger, G., Harel, M., Giles, K., Toker, L., Velan, B., Lazar, A., Kronman, C., Barak, D., Ariel, N., Shafferman, A., Silman, I., & Sussman, J. L. (2000). Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II. Acta Crystallographica Section D: Biological Crystallography, 56(11), 1385-1394. https://doi.org/10.1107/S0907444900010659
  29. Kuca, K., Musilek, K., Jun, D., Karasova, J., Soukup, O., Pejchal, J., & Hrabinova, M. (2013). Structure-activity relationship for the reactivators of acetylcholinesterase inhibited by nerve agent VX. Medicinal Chemistry, 9(5), 689-693. https://doi.org/10.2174/1573406411309050008
  30. Lotti, M. (2010). Clinical toxicology of anticholinesterase agents in humans. In R. Krieger (Ed.), Hayes’ Handbook of Pesticide Toxicology (pp. 1543-1589). Elsevier Inc.
  31. Mallender, W. D., Szegletes, T., & Rosenberry, T. L. (2000). Acetylthiocholine binds to Asp74 at the peripheral site of human acetylcholinesterase as the first step in the catalytic pathway. Biochemistry, 39(26), 7753-7763. https://doi.org/10.1021/bi000210o
  32. Matos, K. S., Mancini, D. T., da Cunha, E. F. F., Kuca, K., Franca, T. C. C., & Ramalho, T. C. (2011). Molecular aspects of the reactivation process of acetylcholinesterase inhibited by cyclosarin. Journal of Brazilian Chemistry Society, 22(10), 1999-2004.
  33. Mercey, G., Renou, J., Verdelet, T., Kliachyna, M., Baati, R., Gillon, E., Arboleas, M., Loiodice, M., Nachon, F., Jean, L., & Renard, P. Y. (2012a). Phenyltetrahydroisoquinoline-pyridinaldoxime conjugates as efficient uncharged reactivators for the dephosphylation of inhibited human acetylcholinesterase. Journal of Medicinal Chemistry, 55(23), 10791-10795. https://doi.org/10.1021/jm3015519
  34. Mercey, G., Verdelet, T., Renou, J., Kliachyna, M., Baati, R., Nachon, F., Jean, L., & Renard, P. Y. (2012b). Reactivators of acetylcholinesterase inhibited by organophosphorus nerve agents. Accounts of Chemical Research, 45(5), 756-766. https://doi.org/10.1021/ar2002864
  35. Morris, G. M., Goodsell, D. S., Halliday, R. S., Huey, R., Hart, W. E., Belew, R. K., & Olson, A. J. (1998). Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of Computational Chemistry, 19(14), 1639-1662. d https://doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B
  36. Mukherjee, S., & Bahadur, R. P. (2018). An account of solvent accessibility in protein-RNA recognition. Scientific Reports, 8(1), 1-13. https://doi.org/10.1038/s41598-018-28373-2
  37. Musilek, K., Jun, D., Cabal, J., Kassa, J., Gunn-Moore, F., & Kuca, K. (2007). Design of a potent reactivator of tabun-inhibited acetylcholinesterases-synthesis and evaluation of (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203). Journal of Medicinal Chemistry, 50(22), 5514-5518.https://doi.org/10.1021/jm070653r
  38. Namba, T., Nolte, C. T., Jackrel, J., & Grob, D. (1971). Poisoning due to organophosphate insecticides. Acute and chronic manifestations. The American Journal of Medicine, 50(4), 475-492. https://doi.org/10.1016/0002-9343(71)90337-8
  39. Ordentlich, A., Barak, D., Sod-Moriah, G., Kaplan, D., Mizrahi, D., Segall, Y., Kronman, C., Karton, Y., Lazar, A., Marcus, D., Velan, B., & Shafferman, A. (2004). Stereoselectivity toward VX is determined by interactions with residues of the acyl pocket as well as of the peripheral anionic site of AChE. Biochemistry, 43(35), 11255-11265. https://doi.org/10.1021/bi0490946
  40. Patil, N., Ranjan, A., Chauhan, A., & Jindal, T. (2018). Mechanistic of organophosphate mediated inhibition of human acetylcholinesterase by molecular docking. JSM Bioinformatics, Genomics and Proteomics, 3(2), 1032-1040.
  41. Qiao, Y., Han, K., & Zhan, C. G. (2014). Reaction pathways and free energy profiles for cholinesterase-catalyzed hydrolysis of 6-monoacetylmorphine. Organic and Biomolecular Chemistry, 12(14), 2214-2227. https://doi.org/10.1039/c3ob42464b
  42. Radić, Z., Sit, R. K., Garcia, E., Zhang, L., Berend, S., Kovarik, Z., Amitai, G., Fokin, V. V., Sharpless, K. B., & Taylor, P. (2013). Mechanism of interaction of novel uncharged, centrally active reactivators with OP-hAChE conjugates. Chemico-Biological Interactions, 203(1), 67-71. https://doi.org/10.1016/j.cbi.2012.08.014
  43. Radić, Z., Sit, R. K., Kovarik, Z., Berend, S., Garcia, E., Zhang, L., Amitai, G., Green, C., Radic, B., Fokin, V. V., Sharpless K. B., & Taylor, P. (2012). Refinement of structural leads for centrally acting oxime reactivators of phosphylated cholinesterases. Journal of Biological Chemistry, 287(15), 11798-11809. https://doi.org/10.1074/jbc.M111.333732
  44. Ranjan, A., Kumar, A., Gulati, K., Thakur, S., & Jindal, T. (2015). Role of aromatic amino acids in stabilizing organophosphate and human acetylcholinesterase complex. Journal of Current Pharma Research, 5(4), 1632-1639. https://doi.org/10.33786/JCPR.2015.V05I04.006
  45. Schaeffer, L. (2008). The role of functional groups in drug–receptor interactions. In C.G. Wermuth, P. Raboisson, D. Aldous, & D. Rognan (Eds.), The practice of medicinal chemistry (pp. 359-378). Elsevier Incorporation. https://doi.org/10.1016/B978-0-12-417205-0.00014-6
  46. Shafferman, A., Velan, B., Ordentlich, A., Kronman, C., Grosfeld, H., Leitner, M., Flashner, Y., Cohen, S., Barak, D., & Ariel, N. (1992). Substrate inhibition of acetylcholinesterase: Residues affecting signal transduction from the surface to the catalytic center. European Molecular Biology Organization Journal, 11(10), 3561-3568. https://doi.org/10.1002/j.1460-2075.1992.tb05439.x
  47. Sit, R. K., Radić, Z., Gerardi, V., Zhang, L., Garcia, E., Katalinić, M., Amitai, G., Kovarik, Z., Fokin, V. V., Sharpless, K. B., & Taylor, P. (2011). New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases. Journal of Biological Chemistry, 286(22), 19422-19430. https://doi.org/10.1074/jbc.M111.230656
  48. Tang, M., Zhou, Y., Xu, W., Li, S., Wang, L., Wei, D., & Qiao, Z. (2013). A novel drug candidate for Alzheimer’s disease treatment: Gx-50 derived from Zanthoxylum bungeanum. Journal of Alzheimer’s Disease, 34(1), 203-213. https://doi.org/10.3233/JAD-121831
  49. Wlodek, S. T., Shen, T., & McCammon, J. A. (2000). Electrostatic steering of substrate to acetylcholinesterase: Analysis of field fluctuations. Biopolymers, 53(3), 265-271. https://doi.org/10.1002/(SICI)1097-0282(200003)53:3<265::AID-BIP6>3.0.CO;2-N
  50. Yellapu, N., Gopal, J., Thulasibabu, R., Gunasekaran, K., & Jambulingam, P. (2015). Screening and identification of inhibitors against glutathione synthetase, a potential drug target of Plasmodium falciparum. Combinatorial Chemistry & High Throughput Screening, 18, 492-504.
  51. Zhang, Y., Zhang, S., Xu, G., Yan, H., Pu, Y., & Zuo, Z. (2016). The discovery of new acetylcholinesterase inhibitors derived from pharmacophore modeling, virtual screening, docking simulation and bioassays. Molecular BioSystems, 12(12), 3734-3742. https://doi.org/10.1039/C6MB00661B
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