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

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.

Comparing fixed and flexible stocking as adaptations to inter-annual rainfall variability in the extensive beef industry of northern Australia

Many beef producers within the extensive cattle industry of northern Australia attempt to maintain a constant herd size from year-to-year (fixed stocking), whereas others adjust stock numbers to varying degrees annually in response to changes in forage supply. The effects of these strategies on pasture condition and cattle productivity cannot easily be assessed by grazing trials. Simulation studies, which include feedbacks of changes to pasture condition on cattle liveweight gain, can extend the results of grazing trials both spatially and temporally. They can compare a large number of strategies, over long periods of time, for a range of climate periods, at locations which differ markedly in climate. This simulation study compared the pasture condition and cattle productivity achieved by fixed stocking at the long-term carrying capacity with that of 55 flexible stocking strategies at 28 locations across Queensland and the Northern Territory. Flexible stocking strategies differed markedly in the degree they increased or decreased cattle stocking rates after good and poor pasture growing seasons, respectively. The 28 locations covered the full range in average annual rainfall and inter-annual rainfall variability experienced across northern Australia. Constrained flexibility, which limited increases in stocking rates after good growing seasons to 10% but decreased them by up to 20% after poor growing seasons, provides sustainable productivity gains for cattle producers in northern Australia. This strategy can improve pasture condition and increase cattle productivity relative to fixed stocking at the long-term carrying capacity, and its capacity to do this was greatest in the semiarid rangeland regions that contain the majority of beef cattle in northern Australia. More flexible stocking strategies, which also increased stocking rates after good growing seasons by only half as much as they decreased them after poor growing seasons, were equally sustainable and more productive than constrained flexibility, but are often impractical at property and industry scales. Strategies with the highest limits (e.g. 70%) for both annual increases and decreases in stocking rates could achieve higher cattle productivity, but this was at the expense of pasture condition and was not sustainable. Constrained flexible stocking, with a 10% limit for increases and a 20% limit for decreases in stocking rates annually, is a risk-averse adaptation to high and unpredictable rainfall variability for the extensive beef industry of northern Australia. © Australian Rangeland Society 2016.