Summary
An extensive conformational search of the potent opioid analgesic, fentanyl, was performed using the semiempirical quantum mechanical method AM1 and the CHARMm potential energy function. A combination of two procedures was used to search the conformational space for fentanyl, which included nested dihedral scans, geometry optimization and molecular dynamics simulation at different temperatures. In addition, the effect of a continuum solvent environment was taken into account by use of appropriate values for the dielectric constant in the CHARMm computations.
The results of the conformational search allowed the determination of the probable conformation of fentanyl in polar and nonpolar solvents and of three candidate conformers for its bioactive form.
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References
Janssen, P.A., Br. J. Anaesth., 34 (1962) 260; U.S. Patent 3141823, Chem. Abstr., 62 (1964) 14634c.
James, I.F. and Goldstein, A., Mol. Pharm. 25 (1984) 337.
Yeadon, M. and Kitchen, I., In Progress in Opioid Research (NIDA Research Monograph 75), Rockville, MD, 1986.
Peeters, O.M., Blaton, N.M., De, Ranter, C.J., Van, Herk, A.M. and Goubitz, K., J. Cryst. Mol. Struct., 9 (1979) 153.
Peeters, O.M., Blaton, N.M. and De, Ranter, C.J., Acta Crystallogr., B35 (1979) 999.
Koch, M.H.J., De, Ranter, C.J., Rolies, M. and Dideberg, O., Acta Crystallogr., B32 (1976) 2529.
Michel, A., Lebrun, B., Evrard, G. and Durant, F., Acta Crystallogr., B38 (1982) 2961.
See references cited in Ref. 16.
Casy, A.F., Hassan, M.M.A., Simmonds, A.B. and Staniforth, D., J. Pharm. Pharmacol. 21 (1969) 434.
Brine, G.A., Boldt, K.G., Huang, P.-T., Sawyer, D.K. and Carroll, F.I., J. Heterocyclic Chem. 26 (1989) 677.
Cheney, B.V., Duchamp, D.J. and Christoffersen, R.E., In Barnett, G., Trsic, M. and Willette, R. (Eds.) QuaSAR Research Monograph 22, National Institute on Drug Abuse, Rockville, MD, 1978, p. 218.
Lobbezoo, M.W., Soudijn, W. and van, Wijngaarden, I., Eur. J. Med. Chem.-Chim. Ther., 15 (1980) 357.
Feinberg, A.P., Creese, I. and Snyder, S.H., Proc. Natl. Acad. Sci. USA, 73 (1976) 4215.
Casy, A.F. and Parfitt, R.T., Opioid Analgesics, 1st edn., Plenum Press, New York, 1986, p. 487.
Lednicer, D. and von, Voigtlander, P.F., J. Med. Chem. 22 (1979) 1158.
Tollenaere, J.P., Moereels, H. and Van, Loon, M., In Jucker, E. (Ed.) Progress in Drug Research, Vol. 30, Birkhäuser Verlag, Basel, 1986, p. 91.
Martin, J. and Andrews, P., J. Comput.-Aided Mol. Design., 1 (1987) 53.
Castiglione-Morelli, M.A., Lelj, F., Pastore, A., Salvadori, S., Tancredi, T., Tomatis, R., Trivellone, E. and Temussi, P.A., J. Med. Chem. 30 (1987) 2067.
Froimowitz, M., In Harris, L.S. (Ed.) Problems of Drug Dependence 1989 (NIDA Research Monograph 95), Rockville, MD, 1989, p. 302.
Brooks, B.R., Bruccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S. and Karplus, M., J. Comp. Chem., 4 (1983) 187.
Polygen Corporation, 200 Fifth Ave., Waltham, MA 02254, U.S.A.
Dewar, M.J.S., Zoebisch, E.G., Healy, E.F. and Stewart, J.J.P., J. Am. Chem. Soc., 107 (1985) 3902.
MOPAC 5.0, QCPE Program 455, Bloomington, IN, U.S.A.
Shanno, D.F., J. Optimization Theory and Applications, 46 (1985) 87.
Fletcher, R. and Powell, M.D., Comput. J., 6 (1963) 163.
Karplus, M. and McCammon, J.A., Annu. Rev. Biochem., 52 (1983) 263.
McCammon, J.A. and Harvey, S.C., Dynamics of Proteins and Nucleic Acids, Cambridge University Press, Cambridge, 1987.
Merck Index, 11th edn., Merck and Co., Inc., Rakway, NJ, 1989.
Gasteiger, J. and Marsili, M., Tetrahedron, 36 (1980) 3219.
Riley, T.N. and Bagley, J.R., J. Med. Chem., 22 (1979) 1167.
Borne, R.F., Law, S.-J., Kapeghian, J.C. and Masten, L.W., J. Pharm. Sci., 69 (1980) 1104.
Fifer, E.K., Davis, W.M. and Borne, R.F., Eur. J. Med. Chem.-Chim. Ther., 19 (1984) 519.
Janssen, P.A., U.S. Patent 3155670, Chem. Abstr., 62P (1965) 7770f; Janssen, P.A., Fr. Patent M2986, Chem. Abstr., 63P (1965) 8372h.
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Cometta-Morini, C., Loew, G.H. Development of a conformational search strategy for flexible ligands: A study of the potent μ-selective opioid analgesic fentanyl. J Computer-Aided Mol Des 5, 335–356 (1991). https://doi.org/10.1007/BF00126667
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DOI: https://doi.org/10.1007/BF00126667