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Synthesis, molecular modelling studies and biological evaluation of new oxoeicosanoid receptor 1 agonists. | LitMetric

Synthesis, molecular modelling studies and biological evaluation of new oxoeicosanoid receptor 1 agonists.

Bioorg Med Chem

Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern N-0316, Oslo, Norway; Faculty of Chemistry, Biology and Food Science, Norwegian University of Life Sciences, P.O. Box 5003, N-1432 Ås, Norway. Electronic address:

Published: July 2018

AI Article Synopsis

  • The study investigates how different chemical compounds related to 5-oxo-ETE interact with the oxoeicosanoid receptor 1 (OXER1), which is involved in inflammation and cancer.
  • Researchers synthesized various derivatives of 5-oxo-ETE and tested their effectiveness in stimulating cellular responses, specifically looking at how well they attract a protein called arrestin.
  • Findings suggest that certain modifications, particularly the methyl ester of 5-oxo-ETE, enhance receptor activation more than the natural compound, while others render the compounds inactive, providing insights for future drug design targeting OXER1.

Article Abstract

The oxoeicosanoid receptor 1 (OXER1) is a member of the G-protein coupled receptors (GPCR) family, and is involved in inflammatory processes and oncogenesis. As such it is an attractive target for pharmacological intervention. The present study aimed to shed light on the molecular fundaments of OXER1 modulation using chemical probes structurally related to the natural agonist 5-oxo-ETE. In a first step, 5-oxo-ETE and its closely related derivatives (5-oxo-EPE and 4-oxo-DHA) were obtained by conducting concise and high-yielding syntheses. The biological activity of obtained compounds was assessed in terms of potency (EC) and efficacy (E) for arrestin recruitment. Finally, molecular modelling and simulation were used to explore binding characteristics of 5-oxo-ETE and derivatives with the aim to rationalize biological activity. Our data suggest that the tested 5-oxo-ETE derivatives (i) insert quickly into the membrane, (ii) access the receptor via transmembrane helices (TMs) 5 and 6 from the membrane side and (iii) drive potency and efficacy by differential interaction with TM5 and 7. Most importantly, we found that the methyl ester of 5-oxo-ETE (1a) showed even a higher maximum response than the natural agonist (1). In contrast, shifting the 5-oxo group into position 4 results in inactive compounds (4-oxo DHA compounds (3) and (3a)). All in all, our study provides relevant structural data that help understanding better OXER1 functionality and its modulation. The structural information presented herein will be useful for designing new lead compounds with desired signalling profiles.

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Source
http://dx.doi.org/10.1016/j.bmc.2018.05.036DOI Listing

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