2. Academic Validation
  3. Structure-activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359

Structure-activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359

  • Eur J Med Chem. 2018 Aug 5;156:847-860. doi: 10.1016/j.ejmech.2018.07.023.
Hang Zhang 1,  Alexander L Nielsen 2,  Michael W Boesgaard 2,  Kasper Harpsøe 2,  Norelle L Daly 3,  Xiao-Feng Xiong 2,  Christina R Underwood 2,  Linda M Haugaard-Kedström 2,  Hans Bräuner-Osborne 2,  David E Gloriam 2,  Kristian Strømgaard 4
Affiliations

Affiliations

  • 1 Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100, Copenhagen, Denmark; Key Laboratory of Advanced Drug, Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
  • 2 Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100, Copenhagen, Denmark.
  • 3 Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.
  • 4 Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100, Copenhagen, Denmark. Electronic address: kristian.stromgaard@sund.ku.dk.
PMID: 30055466 DOI: 10.1016/j.ejmech.2018.07.023
Abstract

G proteins are key mediators in the signaling of G protein-coupled receptors and involved in a plethora of important physiological processes. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known selective inhibitors of the Gq protein subfamily. So far, all reported YM-254890 and FR900359 analogs show no inhibition of other G protein subtypes except the Gq, G11 and G14 proteins. Here we report the rationalization of the high potency of FR900359 and efforts towards understanding the G protein subtype selectivity by synthesis of a collection of structurally and stereochemically diverse analogs of YM-254890 using an efficient synthetic protocol. We performed the first conformational study of YM-254890 in aqueous solution by NMR spectroscopy and replica exchange molecular dynamics, which suggested that the combined contribution of residues with appropriate size, stereochemistry and conformational stability are critical for inhibitory potency. Moreover, in addition to the fit of the binding pocket, more factors should be taken into consideration for the development of compounds targeting other G proteins.

Keywords

Cyclic depsipeptides; G proteins; SAR studies.

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