Three-dimensional common-feature hypotheses for Toll-like receptor 7 agonists

doi:10.5246/jcps.2013.02.020

Abstract

Abstract:

Toll-like receptor 7 (TLR7), the best known TLRs, has been demonstrated to be useful in fighting against infectious disease. In our study, three-dimensional (3D) pharmacophore models were constructed from a set of 5 TLR7 agonists. Among the 10 common-featured models generated by program Discovery Studio/HipHop, a hypothesis (Hypo2) including one hydrogen-bond donor (D), one hydrogen-bond acceptor (A), and two hydrophobic (H) features was considered to be important in evaluating the ligands with TLR7 agonistic activity. The obtained pharmacophore model was further validated using a set of test molecules and the Catalyst TLR7-agonist-subset database. Hypo2 has been shown to identify a range of highly potent TLR7 agonists. Finally, the obtained pharmacophore was further validated using docking studies. Taken together, this model can be utilized as a guide for future studies to design the structurally novel TLR7 agonists.

Key words: Toll-like receptor 7, Agonist, Common-feature hypothesis, Molecular docking

CLC Number:

R916

Supporting:

Shiguang Qi, Hui Yu, Hongwei Jin, Zhanli Wang^*. Three-dimensional common-feature hypotheses for Toll-like receptor 7 agonists [J]. , DOI: 10.5246/jcps.2013.02.020.

References

[1] Akira, S.; Uematsu, S.; Takeuchi, O. Cell. 2006, 124, 783-801.
[2] Tabeta, K.; Georgel, P.; Janssen, E.; Du, X.; Hoebe, K.; Crozat, K.; Mudd, S.; Shamel, L.; Sovath, S.; Goode, J.; Alexopoulou, L.; Flavell, R.A.; Beutler, B. Proc. Natl. Acad. Sci. USA. 2004, 101, 3516-3521.
[3] Chen, K.Q.; Huang, J.; Gong, W.H.; Iribarren, P.; Dunlop, N.M.; Wang, J.M. Int. Immunopharmacol. 2007, 7, 1271-1285.
[4] Yu, H.; Wang, Z.; Sun, G.; Yu, Y. Curr. Med. Chem. 2012, 19, 1365-1377.
[5] Lee, J.; Chuang, T.H.; Redecke, V.; She, L.; Pitha, P.M.; Carson, D.A.; Raz, E.; Cottam, H.B. Proc. Natl. Acad. Sci. USA. 2003, 100, 6646-6651.
[6] Heil, F.; Ahmad-Nejad, P.; Hemmi, H.; Hochrein, H.; Ampenberger, F.; Gellert, T.; Dietrich, H.; Lipford, G.; Takeda, K.; Akira, S.; Wagner, H.; Bauer, S. Eur. J. Immunol. 2003, 33, 2987-2997.
[7] Kurimoto, A.; Hashimoto, K.; Nakamura, T.; Norimura, K.; Ogita, H.; Takaku, H.; Bonnert, R.; McInally, T.; Wada, H.; Isobe, Y. J. Med. Chem. 2010, 53, 2964-2972.
[8] Pryde, D.C.; Tran, T.D.; Jones, P.; Parsons, G.C.; Bish, G.; Adam, F.M.; Smith, M.C.; Hay, D.; Paradowski, M.; Proctor, K.J.W.; Parkinson, T.; Laxton, C.; Fox, D.N.A.; Horscroft, N.J.; Ciaramella, G.; Jones, H.M.; Duckworth, J.; Benson, N.; Harrison, A.; Webster, R. Med. Chem. Commun. 2011, 2, 185-189.
[9] Tran, T.D.; Pryde, D.C.; Jones, P.; Adam, F.M.; Benson, N.; Bish, G.; Calo, F.; Ciaramella, G.; Dixon, R.; Duckworth, J.; Fox, D.N.; Hay, D.A.; Hitchin, J.; Horscroft, N.; Howard, M.; Gardner, I.; Jones, H.M.; Laxton, C.; Parkinson, T.; Parsons, G.; Proctor, K.; Smith, M.C.; Smith, N.; Thomas, A. Bioorg. Med. Chem. Lett. 2011, 21, 2389-2393.
[10] Wei, T.; Gong, J.; Jamitzky, F.; Heckl, W.M.; Stark, R.W. Protein Sci. 2009, 18, 1684-1691.
[11] Gong, J.; Wei, T.; Zhang, N.; Jamitzky, F.; Heckl, W.M. Rössle, S.C.; Stark, R.W. J. Mol. Model. 2010, 16, 1283-1289.
[12] Feig, M.; Brooks, C.L. Curr. Opin. Struct. Biol. 2004, 14, 217-224.
[13] Laskoswki, R.A.; MacArthur, M.W.; Moss, D.S.; Thorton, J.M. J. Appl. Crystallogr. 1993, 26, 283-291.
[14] Govindaraj, R.G.; Manavalan, B.; Basith, S.; Choi, S. PLoS One. 2011, 6, e25118.
[15] Diller, D.J.; Merz, K.M.Jr. Proteins. 2001, 43, 113-124.