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Mapping of the active site of alcohol dehydrogenase with low-molecular ligands

Abstract

In search of an active alcohol dehydrogenase inhibitor, the structure of which may serve as the basis for a potential drug design, the active site of alcohol dehydrogenase containing NAD and Zn2+ ions was mapped using the method of molecular mechanics. Molecular docking was performed using a number of ligands containing characteristic functional groups: formate ion, ammonia, ammonium ion, methanol, and methylamine. Sites of preferable binding were revealed for each ligand and arranged in order of decreasing energy of binding to the enzyme. A comparison of the predicted ligand-binding sites and the experimental data on the location of water and inhibitor binding sites in the known structures of corresponding alcohol dehydrogenase complexes indicated a coincidence of the complex formation sites, which confirms the validity of the method and provides the requirements for a highly effective inhibitor (the pharmacophore model).

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Abbreviations

AS:

active site

References

  1. Porodenko, V.A., Varshavets, N.P., and Perova, T.P.,Sud.-Med. Ekspertiza, 1989, vol. 32, pp. 61–62.

    CAS  Google Scholar 

  2. Anderson, T.J., Shuaib, A., and Becker, W.J.,Can. J. Neurol. Sci., 1989, vol. 16, pp. 432–435.

    PubMed  CAS  Google Scholar 

  3. Puka, J. and Szajewski, J.,Pol. Arch. Med. Wewn., 1988, vol. 80, pp. 88–98.

    PubMed  CAS  Google Scholar 

  4. Momont, S.L. and Dahlberg, P.J.,Wis. Med. J., 1989, vol. 88, pp. 16–20.

    PubMed  CAS  Google Scholar 

  5. Kozhemyakin, L.A., Zelenin, K.N., Bonitenko, Yu.Yu., Ivanova, L.I., Ershov, A.Yu., Zemlyanoi, A.V., and Korolyuk, M.A.,Vopr. Med. Khim., 1990, vol. 36, pp. 67–69.

    CAS  Google Scholar 

  6. Li, T.K., Bosron, W.F., Dafeldecker, W.P., Lange, L.G., and Vallee, B.L.,Proc. Natl. Acad. Sci. USA, 1977, vol. 74, pp. 4378–4381.

    PubMed  Article  CAS  Google Scholar 

  7. Bohm, H.-J.,J. Comp. Aided Mol. Des., 1992, vol. 6, pp. 593–606.

    Article  CAS  Google Scholar 

  8. Caflisch, A., Miranker, A., and Karplus, M.,J. Med. Chem., 1993, vol. 36, pp. 2142–2167.

    PubMed  Article  CAS  Google Scholar 

  9. Eisen, M.B., Wiley, D.C., Karplus, M., and Hubbard, R.E.,Proteins, 1994, vol. 19, pp. 199–221.

    PubMed  Article  CAS  Google Scholar 

  10. Xie, P., Parsons, S.H., Speckhard, D.C., Bosron, W.F., and Hurley, T.D.,J. Biol. Chem., 1997, vol. 272, pp. 18558–18563.

    PubMed  Article  CAS  Google Scholar 

  11. Abagyan, R., Totrov, M., and Kuznetsov, D.,J. Comput. Chem., 1994, vol. 15, pp. 488–506.

    Article  CAS  Google Scholar 

  12. Luescher, I., Romero, P., Kuznetsov, D., Rimoldi, D., Coulie, P., Cerrotini, J.-C., and Jongeneel, V.,J. Biol. Chem., 1996, vol. 271, pp. 12 463–12 471.

    CAS  Google Scholar 

  13. Anjuere, F., Kuznetsov, D., Romero, P., Cerrotini, J.-C., Jongeneel, V., and Luescher, I.,J. Biol. Chem., 1997, vol. 272, pp. 8505–8514.

    PubMed  Article  CAS  Google Scholar 

  14. Momany, F.A., McGuire, R.F., Burgess, A.W., and Scheraga, H.A.,J. Phys. Chem., 1975, vol. 7, pp. 2361–2380.

    Article  Google Scholar 

  15. Nemethy, M.S., Pottle, M.S., and Scheraga, H.A.,J. Phys. Chem., 1983, vol. 87, pp. 1833–1851.

    Article  Google Scholar 

  16. Sippl, M.J., Nemethy, G., and Scheraga, H.A.,J. Phys. Chem., 1984, vol. 88, pp. 6231–6233.

    Article  CAS  Google Scholar 

  17. Nemethy, G., Gibson, K.D., Palmer, K.A., Yoon, C.N., Paterlini, G., Zagari, A., Rumsey, S., and Scheraga, H.A.,J. Phys. Chem., 1992, vol. 96, pp. 6472–6484.

    Article  CAS  Google Scholar 

  18. Chau, P.L. and Dean, P.M.,J. Comp. Aided Mol. Des., 1992, vol. 6, pp. 407–426.

    Article  CAS  Google Scholar 

  19. Froimowitz, M.,BioTechniques, 1993, vol. 14, pp. 1010–1013.

    PubMed  CAS  Google Scholar 

  20. Metropolis, N.A., Rosenbluth, A.W., Rosenbluth, N.M., Teller, A.H., and Teller, E.,J. Chem. Phys., 1953, vol. 21, pp. 1085–1090.

    Article  Google Scholar 

  21. Holm, L. and Sander, Ch.,J. Mol. Biol., 1993, vol. 233, pp. 123–138.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to A. S. Kutsenko.

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Kutsenko, A.S., Kuznetsov, D.A., Poroikov, V.V. et al. Mapping of the active site of alcohol dehydrogenase with low-molecular ligands. Russ J Bioorg Chem 26, 157–163 (2000). https://doi.org/10.1007/BF02786340

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  • DOI: https://doi.org/10.1007/BF02786340

key words

  • alcohol dehydrogenase
  • proteins
  • structure
  • ligands
  • docking
  • molecular mechanics