Summary
To elucidate the conformation of receptor-associated prostacyclin (PGI2), we first performed structure-activity correlation analysis of over 200 PGI2 analogues and derived from this analysis several crucial features pertaining to structural requirements for PGI2 activity [Ah-lim Tsai and Kenneth K. Wu, Eicosanoids, 2 (1989) 131–143]. These structural features proved to be useful guidelines for selecting ‘model molecules’ for further investigations by molecular mechanics. By properly selecting four analogues with either rigid or uniquely oriented α-side chain structure for geometric fitting, we succeeded in maximally minimizing the degree of freedom of the carboxylate terminus of PGI2. We were able to define the spatial relationship among the four critical functional groups, i.e., C1-COOH, C6a-O, C11-OH and C15-OH. More information is needed, however, to define the geometry of the ω-side chain, particularly for the moiety beyond C15. Nevertheless, results from structure-activity correlation analysis and molecular modeling provide useful information regarding the conformation of receptor-associated PGI2, which assumes an ‘elongated’ conformation instead of the traditional ‘hairpin’ structure.
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References
Gryglewski, R.J.. In: Gryglewski, R.J. and Stock, G. (Eds.), Prostacyclin and its Stable Analogue Iloprost, Springer-Verlag, Berlin, 1987, pp. 3–9.
Moncada, S. and Vane, J.R. In: Kharasch, N. and Fried, J. (Eds.), Biochemical Aspects of Prostaglandins and Thromboxanes, Academic Press, New York, 1977, pp. 155–177.
Moncada, S., Gryglewski, R., Bunting, S. and Vane, J.R., Nature (Lond.), 263 (1976) 663.
Siegl, A.M., Smith, J.B., Silver, M.J., Nicolaou, K.C. and Ahern, D.J., J. Clin. Invest., 63 (1979) 215.
Leigh, P.J., Cramp, W.A. and MacDermot, J., J. Biol. Chem., 259 (1984) 12431.
Tsai, A.L., Hsu, M.J., Vijjeswarapu, H. and Wu, K.K., J. Biol. Chem., 264 (1989) 61.
DenKelder, G.M.D., J. Comput.-Aided Mol. Design, 1 (1987) 257.
Crippen, G.M., J. Med. Chem., 22 (1979) 988.
Aristoff, P.A. In: Pike, J.E. and MortonJr., R. (Eds.), Advances in Prostaglandin, Thromboxane and Leukotriene Research, Raven Press, New York, 1985, pp. 309–383.
Nickolson, R.C., Town, M.J. and Vorbrüggen, H., Med. Res. Rev., 5 (1985) 1.
Muchowski, J.M. In: Willis, A.L. (Ed.), Handbook of Eicosanoids: Prostaglandins and Related Lipids, Chemical and Biochemical Aspects. Vol. 1, Part B, CRC Press, Boca Raton, FL, 1987, pp. 42–75.
MacIntyre, D.E. In: Gordon, J.I. (Ed.), Platelets in Biology and Pathology, Vol. 2, Elsevier/North-Holland, Amsterdam, 1981, pp. 211–244.
Taylor, R.J.K. In: Roberts, S.M. and Scheimann, F. (Eds.), New Synthetic Routes to Prostaglandins and Thromboxanes, Academic Press, London, 1982, pp. 191–237.
Tsai, A.L. and Wu, K.K., Eicosanoids, 2 (1989) 131.
Newkome, G.R., J. Am. Chem. Soc., 110 (1988) 325.
Johnson, R.A., Morton, D.R., Kinner, J.H., Gorman, R.R., McGuire, J.C., Sun, F.F., Whittaker, N., Bunting, S., Salmon, J., Moncada, S. and Vane, J.R., Prostaglandins, 12 (1976) 915.
Kluge, A.F., Kertesz, D.J., O-Yang, D. and Wu, H.Y., J. Org. Chem., 52 (1987) 2860.
Scholkens, B.A., Bartmann, W., Beck, G., Lerch, U., Konz, E. and Weithmann, U., Prostaglandins Med., 3 (1979) 7.
Kawasaki, A., Katsube, N., Sakaguchi, K., Hiraku, S. and Tsuboshima, N., Vth International Conference on Prostaglandins, Florence, Italy, 1982, p. 314 (Abstr.).
Flohè, L., Böhlke, H., Frankus, E., Kim, S.M.A., Lintz, W., Loschen, G., Michel, G., Müller, B., Schneider, J., Seipp, U., Vollenberg, W. and Wilsmann, K., Arzneim.-Forsch./Drug Res., 33 (1982) 1240.
Blair, I.A., Hensby, C.N. and MacDermot, J., Br. J. Pharmacol., 69 (1980) 519.
Bartmann, W. and Beck, G., Angew. Chem. Int. Ed. Engl., 21 (1982) 751.
Tsai, A.L., Vijjeswarapu, H. and Wu, K.K., Biochim. Biophys. Acta, 942 (1988) 220.
Langs, D.A., Erman, M. and DeTitta, G.T., Science, 192 (1977) 1003.
Anderson, N.H., Imamoto, S., Subramanian, N., Picker, D.H., Ladner, D.W., De, B., Tynan, S.S., Eggerman, T.L., Harker, L.A., Robertson, R.P., Oien, H.G. and Rao, C.V., Prostaglandins, 22 (1981) 841.
DeTitta, G.T., Science, 191 (1976) 1271.
Langs, D.A., DeTitta, G.T., Erman, M.G. and Fortier, S. In: Samuelsson, B., Ramwell, P.W. and Paoletti, R. (Eds.), Advances in Prostaglandin and Thromboxane Research, Vol. 6, Raven Press, New York, 1980, pp. 477–480.
Vorbrüggen, H. and Skuballa, W. In: Mutschler, E. and Winterfeldt, E. (Eds.), Trends in Medicinal Chemistry, VCH Publishers, New York, 1988, pp. 393–395.
Stezowski, J.J., Flohè, L. and Böhlke, H., J. Chem. Soc. Chem. Commun. (1983) 1315.
Kotovych, G., Aarts, G.H.M., Nakashima, T.T. and Bigam, G., Can. J. Chem., 58 (1980) 974.
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Tsai, Al., Strobel-Jager, E. & Wu, K.K. Conformation of receptor-associated PGI2: An investigation by molecular modeling. J Computer-Aided Mol Des 5, 135–148 (1991). https://doi.org/10.1007/BF00129752
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DOI: https://doi.org/10.1007/BF00129752