Abstract
Three neurokinin (NK) antagonist pharmacophore models (Models 1–3) accounting for hydrogen bonding groups in the `head' and `tail' of NK receptor ligands have been developed by use of a new procedure for treatment of hydrogen bonds during superimposition. Instead of modelling the hydrogen bond acceptor vector in the strict direction of the lone pair, an angle is allowed between the hydrogen bond acceptor direction and the ideal lone pair direction. This approach adds flexibility to hydrogen bond directions and produces more realistic RMS values. By using this approach, two novel pharmacophore models were derived (Models 2 and 3) and a hydrogen bond acceptor was added to a previously published NK2 pharmacophore model [Poulsen et al., J. Comput.-Aided Mol. Design, 16 (2002) 273] (Model 1). Model 2 as well as Model 3 are described by seven pharmacophore elements: three hydrophobic groups, three hydrogen bond acceptors and a hydrogen bond donor. Model 1 contains the same hydrophobic groups and hydrogen bond donor as Models 2 and 3, but only one hydrogen bond acceptor. The hydrogen bond acceptors and donor are represented as vectors. Two of the hydrophobic groups are always aromatic rings whereas the other hydrophobic group can be either aromatic or aliphatic. In Model 1 the antagonists bind in an extended conformation with two aromatic rings in a parallel displaced and tilted conformation. Model 2 has the same two aromatic rings in a parallel displaced conformation whereas Model 3 has the rings in an edge to face conformation. The pharmacophore models were evaluated using both a structure (NK receptor homology models) and a ligand based approach. By use of exhaustive conformational analysis (MMFFs force field and the GB/SA hydration model) and least-squares molecular superimposition studies, 21 non-peptide antagonists from several structurally diverse classes were fitted to the pharmacophore models. More antagonists could be fitted to Model 2 with a low RMS and a low conformational energy penalty than to Models 1 and 3. Pharmacophore Model 2 was also able to explain the NK1, NK2 and NK3 subtype selectivity of the compounds fitted to the model. Three NK 7TM receptor models were constructed, one for each receptor subtype. The location of the antagonist binding site in the three NK receptor models is identical. Compounds fitted to pharmacophore Model 2 could be docked into the NK1, NK2 and NK3 receptor models after adjustment of the conformation of the flexible linker connecting the head and tail. Models 1 and 3 are not compatible with the receptor models.
Similar content being viewed by others
References
Regoli, D., Boudon, A. and Fauchere, J.L. Pharmacol. Rev., 46 (1994) 551.
Poulsen, A., Liljefors, T., Gundertofte, K. and Bjørnholm, B., J. Comput.-Aided Mol. Des., 16 (2002) 273.
Williams, D.E., Acta Crystallogr., A36 (1980) 715.
Greenfeder, S., Cheewatrakoolpong, B., Billah, M., Egan, R.W., Keene, E., Murgolo, N.J. and Anthes, J.C., Bioorg. Med. Chem., 7 (1999) 2867.
Blaney, F.E., Raveglia, L.F., Artico, M., Cavagnera, S., Dar-tois, C., Farina, C., Grugni, M., Gagliardi, S., Luttmann, M.A., Martinelli, M., Nadler, G.M., Parini, C., Petrillo, P., Sarau, H.M., Scheideler, M.A., Hay, D.W. and Giardina, G.A., J. Med. Chem., 44 (2001) 1675.
Palczewski, K., Kumasaka, T., Hori, T., Behnke, C.A., Motoshima, H., Fox, B.A., Le, T., Teller, D.C., Okada, T., Stenkamp, R.E., Yamamoto, M. and Miyano, M., Science, 289 (2000) 739. b. Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. and Bourne, P.E., Nucleic Acids Res., 28 (2000) 235. http://www.rcsb.org/pdb/
Elling, C.E., Thirstrup, K., Nielsen, S.M., Hjorth, S.A. and Schwartz, T.W., Fold. Des., 2 (1997) S76.
Elling, C.E. and Schwartz, T.W., EMBO J., 15 (1996) 6213.
Donnelly, D., Maudsley, S., Gent, J.P., Moser, R.N., Hurrell, C.R. and Findlay, J.B., Biochem. J., 339 ( Pt 1) (1999) 55.
Lundstrom, K., Hawcock, A.B., Vargas, A., Ward, P., Thomas, P. and Naylor, A., Eur. J. Pharmacol., 337 (1997) 73.
Cascieri, M.A., MacLeod, A.M., Underwood, D., Shiao, L.L., Ber, E., Sadowski, S., Yu, H., Merchant, K.J., Swain, C.J. and Strader, C.D., J. Biol. Chem., 269 (1994) 6587.
Fong, T.M., Yu, H., Cascieri, M.A., Underwood, D., Swain, C.J. and Strader, C.D., J. Biol. Chem., 269 (1994) 2728.
Fong, T.M., Yu, H., Cascieri, M.A., Underwood, D., Swain, C.J. and Strader, C.D., J. Biol. Chem., 269 (1994) 14957.
Ali, M.A., Bhogal, N., Fishwick, C.W. and Findlay, J.B., Bioorg. Med. Chem. Lett., 11 (2001) 819.
Giolitti, A., Cucchi, P., Renzetti, A.R., Rotondaro, L., Zap-pitelli, S. and Maggi, C.A., Neuropharmacology, 39 (2000) 1422.
Henderson, R., Baldwin, J.M., Ceska, T.A., Zemlin, F., Beck-mann, E. and Downing, K.H., J. Mol. Biol., 213 (1990) (pp899).
Baldwin, J.M., Schertler, G.F. and Unger, V.M., J. Mol. Biol., 272 (1997) 144.
Unger, V.M., Hargrave, P.A., Baldwin, J.M. and Schertler, G.F., Nature, 389 (1997) 203.
Macromodel 7.1. Schrödinger Inc., Portland, OR.
Hasel, T.F., Hendrickson, T.F. and Still, W.C., Tetrahedron Comput. Methods, 1 (1988) 103.
Still, W.C., Tempczyk, A., Hawley, R.C. and Hendrickson, T., J. Am. Chem. Soc., 112 (1990) 6127.
Boström, J., Norrby, P.-O. and Liljefors, T., J. Comput.-Aided Mol. Des., 12 (1998) 383.
Jaguar 4.1. Schrödinger Inc., Portland, OR.
Horn, F., Weare, J., Beukers, M.W., Hörsch, S., Bairoch, A., Chen, W., Edvardsen, Ø., Campagne, F. and Vriend, G., Nucleic Acids Res., 26 (1998) 275.
Pogozheva, I.D., College of Pharmacy, University of Michigan, Ann Arbor, MI, 2002.
Pogozheva, I.D., Lomize, A.L. and Mosberg, H.I., Biophys. J., 72 (1997) 1963.
Guntert, P., Braun, W. and Wüthrich, K., J. Mol. Biol., 217 (1991) 517.
Huang, R.R., Vicario, P.P., Strader, C.D. and Fong, T.M., Biochemistry, 34 (1995) 10048.
CHARMm. Accelrys Inc., San Diego, CA.
Sjöberg, P. In Van de Waterbeemd, H., Testa, B. and Folkers, G., (Eds.), Computer-Assisted Lead Finding and Optimiz-ation. Verlag Helvetica Chimica Acta, Basel, Switzerland, 1997, p. 83.
Lommerse, J.P.M., Price, S.L. and Taylor, R., J. Comput. Chem., 18 (1997) 757.
Edmonds-Alt, X., Proietto, V., Broeck, D.V., Vilain, P., Ad-venier, C., Neliat, G., Fur, G.L. and Brelière, J.-C., Bioorg. Med. Chem. Lett., 3 (1993) 925.
Kubota, H., Kakefuda, A., Okamoto, Y., Fujii, M., Yamamoto, O., Yamagiwa, Y., Orita, M., Ikeda, K., Takeuchi, M., Shibanuma, T. and Isomura, Y., Chem. Pharm. Bull. (Tokyo), 46 (1998) 1538.
Burkholder, T.P., Kudlacz, E.M., Maynard, G.D., Liu, X.G., Le, T.-B., Webster, M.E., Horgan, S.W., Wenstrup, D.L., Fre-und, D.W., Boyer, F., Bratton, L., Gross, R.S., Knippenberg, R.W., Logan, D.E., Jones, B.K. and Chen, T.-M., Bioorg. Med. Chem. Lett., 7 (1997) 2531.
Shih, N.Y., Albanese, M., Anthes, J.C., Carruthers, N.I., Grice, C.A., Lin, L., Mangiaracina, P., Reichard, G.A., Schwerdt, J., Seidl, V., Wong, S.C. and Piwinski, J.J., Bioorg. Med. Chem. Lett., 12 (2002) 141.
Burkholder, T P., Kudlacz, E.M., Le, T.-B., Knippenberg, R.W., Shatzer, S.A., Maynard, G.D., Webster, M.E. and Horgan, S.W., Bioorg. Med. Chem. Lett., 6 (1996) 951.
Giardina, G.A.M., Raveglia, L.F. and Grugni, M., Drugs Future, 22 (1997) 1235.
Shah, S.K., Patent US5434158, 1995.
Kubota, H., Kakefuda, A., Nagaoka, H., Yamamoto, O., Ikeda, K., Takeuchi, M., Shibanuma, T. and Isomura, Y., Chem. Pharm. Bull. (Tokyo), 46 (1998) 242.
Burkholder, T.P., Kudlacz, E.M., Le, T.-B. and Maynard, G.D., Patent US5824690, 1998.
Giardina, G.A.M., Grugni, M., Graziani, D. and Raveglia, L.F., Patent WO-09852942, 1998.
Kubota, H., Fujii, M., Ikeda, K., Takeuchi, M., Shibanuma, T. and Isomura, Y., Chem. Pharm. Bull. (Tokyo), 46 (1998) 351.
Mackenzie, A.R., Marchington, A.P., Middelton, D.S. and Meadows, S.D., Patent WO9719942, 1997.
Miller, S.C., Jacobs, R.T. and Shenvi, A.B., Patent EP-739891, 1996.
Nishi, T., Fukazawa, T., Ishibashi, K., Nakajima, K., Sugioka, Y., Iio, Y., Kurata, H., Itoh, K., Mukaiyama, O., Satoh, Y. and Yamaguchi, T., Bioorg. Med. Chem. Lett., 9 (1999) 875.
Shankar, B.B., Patent WO-09818785, 1998.
Selway, C.N. and Terrett, N.K., Bioorg. Med. Chem., 4 (1996) 645.
McCormick, K.D. and Lupo, A.T., Patent WO-09639383, 1996.
Shankar, B.B., Patent US5688960, 1997.
Smith, P.W., Cooper, A.W., Bell, R., Beresford, I.J., Gore, P.M., McElroy, A.B., Pritchard, J.M., Saez, V., Taylor, N.R. and Sheldrick, R.L., J. Med. Chem., 38 (1995) 3772.
Cooper, A.W.J., Adams, H.S., Bell, R., Gore, P.M., McElroy, A.B., Pritchard, J.M., Smith, P.W. and Ward, P., Bioorg. Med. Chem. Lett., 4 (1994) 1951.
Reichard, G., Aslain, R., Alaimo, C., Kirkup, M. and Lupo, A., Patent US5696267, 1997.
Mackenzie, A.R., Marchington, A.P., Meadows, S.D. and Middleton, D.S., Patent EP-791592, 1997.
Mackenzie, A.R., Marchington, A.P., Middelton, D.S. and Meadows, S.D., Patent WP9727185, 1997.
Burkholder, T.P., Maynard, G.D. and Kudlacz, E.M., Patent WO9827086, 1998.
Oka, H., Lida, M., Sato, Y. and Honda, M., Patent WO9900388, 1999.
Harrison, T., Korsgaard, M.P., Swain, C.J., Cascieri, M.A., Sadowski, S. and Seabrook, G.R., Bioorg. Med. Chem. Lett., 8 (1998) 1343.
Monaghan, S.M., Alker, D. and Burns, C.J., Patent WO9857972, 1998.
Shenvi, A.B., Jacobs, R.T., Miller, S.C., Macht, C.J. and Veale, C.A., Patent WO-09516682, 1995.
Gerspacher, M. and von Sprecher, A., Drugs Future, 24 (1999) 883.
Burkholder, T.P., Bioorg. Med. Chem. Lett., 7 (1997) 2531.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Poulsen, A., Bjørnholm, B., Gundertofte, K. et al. Pharmacophore and receptor models for neurokinin receptors. J Comput Aided Mol Des 17, 765–783 (2003). https://doi.org/10.1023/B:JCAM.0000017497.58165.d8
Issue Date:
DOI: https://doi.org/10.1023/B:JCAM.0000017497.58165.d8