J Appl Biomed 9:163-171, 2011 | DOI: 10.2478/v10136-009-0037-1

Docking studies and effects of syn-anti isomery of oximes derived from pyridine imidazol bicycled systems as potential human acetylcholinesterase reactivators

Ana Paula Guimarães1,2, Tanos Celmar Costa França1, Teodorico Castro Ramalho2,*, Magdalena Nascimento Rennó3, Elaine Fontes Ferreira da Cunha2, Karina Silvia Matos2, Daiana Teixeira Mancini2, Kamil Kuèa4,5
1 Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense, Military Institute of Engineering, Rio de Janeiro, Brazil
2 Chemistry Department, Federal University of Lavras, Lavras, Brazil
3 Pharmacy Faculty, Federal University of Rio de Janeiro, Campus Macaé, Macaé, Brazil
4 Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Hradec Králové, Czech Republic
5 University Hospital, Hradec Králové, Czech Republic

In order to contribute to a better understanding of the mechanism of action of oximes, we evaluated the affinities of 10 new oximes, derived from pyridine-imidazol bicycled systems, for human acetylcholinesterase (HssAChE) complexed with tabun, by estimating their docking energy values and comparing of the values obtained to known oximes using the software Molegro Virtual Docker (MVD)®. We evaluated the influence of the position of the oxime group as substituent in the structures and, also, the influence of the oxime group syn-anti isomery on the docking score values for all the molecules studied. Results suggest that: the affinities of the 10 new oximes for the tabun inhibited HssAChE active site are better than pralidoxime's and similar to trimedoxime's; the meta-pralidoxime could have more affinity for the HssAChE active site and the oximes' anti isomers could present slightly better affinities for the HssAChE active site than the syn isomers.

Keywords: acetylcholinesterase; docking studies; oximes; neurotoxic agents; theoretical calculation

Received: November 15, 2010; Revised: February 10, 2011; Published: July 31, 2011  Show citation

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Guimarães AP, Celmar Costa França T, Ramalho TC, Nascimento Rennó M, da Cunha EFF, Matos KS, et al.. Docking studies and effects of syn-anti isomery of oximes derived from pyridine imidazol bicycled systems as potential human acetylcholinesterase reactivators. J Appl Biomed. 2011;9(3):163-171. doi: 10.2478/v10136-009-0037-1.
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    References

    1. Bartosova L, Kuca K, Jun D, Kunesova G. Bispyridinium oximes as antidotal treatment of cyclosarin poisoning - in vitro and in vivo testing. Internat J Tox. 24: 399-402, 2005. Go to original source... Go to PubMed...
    2. Bay E, Krop S, Yates LF. Chemotherapeutic effectiveness of 1,1'-trimethylene bis (4-formylpyridinium bromide) di-oxime (TMB-4) in experimental anticholinesterase poisoning. Proc Soc Exp Biol Med. 98: 107-110, 1958. Go to original source... Go to PubMed...
    3. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat T N, Weissig H, Shindyalov IN, Bourne PE. The protein data bank. Nucleic Acids Res. 28: 235-242, 2000. Go to original source... Go to PubMed...
    4. Bernstein FC, Koetzle TF, Williams GJ, Meyer EE, Brice MD, Rodgers JR, Kennard O, Shimanouchi T, Tasumi M. The protein data bank. A computer-based archival file for macromolecular structures. J Mol Biol. 112: 535-542, 1977. Go to original source... Go to PubMed...
    5. Castro AT, Figueroa-Villar JD. Molecular structure, conformational analysis and charge distribution of pralidoxime: Ab initio and DFT studies. Int J Quantum Chem. 89: 135-146, 2002. Go to original source...
    6. Delfino RT, Figueroa-Villar JD. Nucleophilic reactivation of sarin-inhibited acetylcholinesterase: A molecular modeling study. J Phys Chem B. 113: 8402-8411, 2009. Go to original source... Go to PubMed...
    7. Delfino RT, Ribeiro TS, Figueroa-Villar JD. Organophosphorus compounds as chemical warfare agents: a review. J Braz Chem Soc. 20: 407-428, 2009. Go to original source...
    8. Ekström F J, Astot C, Pang YP. Novel nerve-agent antidote design based on crystallographic and mass spectrometric analyses of tabun-conjugated acetylcholinesterase in complex with antidotes, Clin Pharmacol Ther. 82: 282-293, 2007. Go to original source... Go to PubMed...
    9. Frisch MJ, Trucks GW, Schlegel HB, Scuseria ES, Pople JA. Gaussian 98 (Revision A.11). Gaussian Pittsburgh 2001.
    10. Gonçalves AS, França TCC, Wilter A, Figueroa-Villar JD. Molecular dynamics of the interaction of pralidoxime and deazapralidoxime with acetylcholinesterase inhibited by the neurotoxic agent tabun. J Braz Chem Soc. 17: 968-975, 2006. Go to original source...
    11. Gonçalves AS, França TCC, Figueroa-Villar JD, Pascutti PG. Conformational analysis of toxogonine, TMB-4 and HI-6 using PM6 and RM1 methods, J Braz Chem Soc. 21: 179-184, 2010. Go to original source...
    12. Hehre WJ, Deppmeier BJ, Klunzinger PE. PC SPARTAN Pro. Wavefunction Inc., Irvine 1999.
    13. Kassa J, Kuca K, Bartosova L, Kunesova G. The development of new structural analogues of oximes for the antidotal treatment of poisoning by nerve agents and the comparison of their reactivating and therapeutic efficacy with currently available oximes. Curr Org Chem. 11: 267-283, 2007. Go to original source...
    14. Kryger G, Harel M, Giles K, Toker L, Velan B, Lazar A, Kronman C, Barak D, Ariel N, Silman I, Shafferman A, Sussman JL. Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II. Acta Crystallogr. 56: 1385-1394, 2000. Go to original source... Go to PubMed...
    15. Ramalho TC, Taft CA. Thermal and solvent effects on the NMR and UV parameters of some bioreductive drugs. J Chem Physics. 123: 054319-054328, 2005. Go to original source... Go to PubMed...
    16. Ramalho TC, França TCC, Rennó MN, Guimarães AP, da Cunha EFF, Kuèa K. Development of new acetylcholinesterase reactivators: Molecular modeling versus in vitro data. Chem Biol Inter. 185: 73-77, 2010. Go to original source... Go to PubMed...
    17. Smirnova OI, E Gurina IL, Zhigalova V, Arestova LS. Toxicity and tolerance of toxogonin, Farmakol Toksikol. 38: 467-470, 1975. Go to PubMed...
    18. Thomsen R, Christensen MH. MolDock: A new technique for high-accuracy molecular docking. J Med Chem. 49: 3315-3321, 2006. Go to original source... Go to PubMed...
    19. Worek F, Aurbek N, Koller M, Becker C, Eyer P, Thiermann H. Kinetic analysis of reactivation and aging of human acetylcholinesterase inhibited by different phosphoramidates. Biochem Pharmacol. 73: 1807-1817, 2007. Go to original source... Go to PubMed...

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