Endomorphin-1 (Tyr-Pro-Trp-Phe-NH P ) is a highly selective and potent agonist of the W W-opioid receptor. To identify structural attributes unique to this opioid peptide and potential sites of recognition, a conformational analysis has been performed using multidimensional NMR and molecular modeling techniques. The spectroscopic results, derived from experiments in both DMSO and water, indicate that endomorphin-1 exists in the cis-and trans-configuration with respect to the Pro-omega bond in approximately 25% and 75% populations, respectively. In DMSO, the cis-configuration adopts a compact sandwich conformation in which the Tyr and Trp aromatic rings pack against the proline ring, whereas the trans-configuration adopts an extended conformation. Although non-random structure was not observed in water, condensed phase molecular dynamics calculations indicate that trans-isomers dominate the population in this higher dielectric medium. Structural comparison of the cis-and trans-configurations with morphine and selective W Wpeptide ligands PL-017 and D-TIPP, as well as the N N-selective peptide ligands TIPP (N N-antagonist, W W-agonist) and DPDPE were also performed and suggest the trans-isomer is likely the bioactive form. A hypothesis is proposed to explain W W-and N Nselectivity based on the presence of spatially distinct selectivity pockets among these ligands.z 1998 Federation of European Biochemical Societies.

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Natural products (NPs) have long been a source of insecticidal crop protection products. Like many macrolide NPs, the spinosyns originated from a soil inhibiting microorganism (Saccharopolyspora spinosa). More than 20 years after initial registration, the spinosyns remain a unique class of NP‐based insect control products that presently encompass two insecticidal active ingredients, spinosad, a naturally occurring mixture of spinosyns, and spinetoram, a semi‐synthetic spinosyn product. The exploration and exploitation of the spinosyns has, unusually, been tied to an array of computational tools including artificial intelligence (AI)‐based quantitative structure activity relationship (QSAR) and most recently computer‐aided modeling and design (CAMD). The AI‐based QSAR directly lead to the discovery of spinetoram, while the CAMD studies have recently resulted in the discovery and building of a series of synthetic spinosyn mimics. The most recent of these synthetic spinosyn mimics show promise as insecticides targeting lepidopteran insect pests as demonstrated by field studies wherein the efficacy has been shown to be comparable to spinosad and spinetoram. These and a range of other aspects related to the exploration of the spinosyns over the past 30 years are reviewed herein. © 2020 Society of Chemical Industry

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