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Synthesis, Binding and Bioactivity of [gamma]-Methylene [gamma]-Lactam Ecdysone Receptor Ligands: Advantages of QSAR Models for Flexible Receptors

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Birru, K.E., Fernley, R.T., Graham, L.D., Grusovin, J., Hill, R.J., Hofmann, A., Howell, L., James, P.J., Jarvis, K.E., Johnson, W.M., Leitner, C., Liepa, A.J., Lovrecz, G.O., Lu, L., Nearn, R.H., O'Driscoll, B.J., Phan, T., Pollard, M., Turner, K.A. and Winkler, D.A. (2010) Synthesis, Binding and Bioactivity of [gamma]-Methylene [gamma]-Lactam Ecdysone Receptor Ligands: Advantages of QSAR Models for Flexible Receptors. Bioorganic & Medicinal Chemistry, 18 (15). pp. 5647-5660.

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Article Link: http://dx.doi.org/10.1016/j.bmc.2010.06.020

Publisher URL: http://www.elsevier.com


Nuclear hormone receptors, such as the ecdysone receptor, often display a large amount of induced fit to ligands. The size and shape of the binding pocket in the EcR subunit changes markedly on ligand binding, making modelling methods such as docking extremely challenging. It is, however, possible to generate excellent 3D QSAR models for a given type of ligand, suggesting that the receptor adopts a relatively restricted number of binding site configurations or [`]attractors'. We describe the synthesis, in vitro binding and selected in vivo toxicity data for [gamma]-methylene [gamma]-lactams, a new class of high-affinity ligands for ecdysone receptors from Bovicola ovis (Phthiraptera) and Lucilia cuprina (Diptera). The results of a 3D QSAR study of the binding of methylene lactams to recombinant ecdysone receptor protein suggest that this class of ligands is indeed recognized by a single conformation of the EcR binding pocket.

Item Type:Article
Corporate Creators:DEEDI
Additional Information:© Crown copyright. © Elsevier Ltd.
Keywords:Biological activity; structure-activity relationships; synthesis; ecdysone receptor; hormone receptors.
Subjects:Veterinary medicine > Diseases of special classes of animals > Sheep and goats
Science > Biology
Live Archive:08 Sep 2010 01:53
Last Modified:03 Sep 2021 16:48

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