2. Academic Validation
  3. In silico discovery of quinoxaline derivatives as novel LRP5/6-sclerostin interaction inhibitors

In silico discovery of quinoxaline derivatives as novel LRP5/6-sclerostin interaction inhibitors

  • Bioorg Med Chem Lett. 2018 Apr 1;28(6):1116-1121. doi: 10.1016/j.bmcl.2018.01.050.
Jiwon Choi 1,  Kyungro Lee 2,  Myeongmo Kang 3,  Sung-Kil Lim 4,  Kyoung Tai No 5
Affiliations

Affiliations

  • 1 Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul 03722, Republic of Korea.
  • 2 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
  • 3 Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
  • 4 Department of Internal Medicine College of Medicine, Yonsei University, Seoul 03722, Republic of Korea. Electronic address: lsk@yhus.ac.
  • 5 Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul 03722, Republic of Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea. Electronic address: ktno@yonsei.ac.kr.
PMID: 29486968 DOI: 10.1016/j.bmcl.2018.01.050
Abstract

The Wnt/β-catenin signaling pathway is a key regulator of bone homeostasis. Sclerostin act as an extracellular inhibitor of canonical Wnt signaling through high-affinity binding to the Wnt co-receptor LRP5/6. Disruption of the interaction between LRP5/6 and sclerostin has been recognized as a therapeutic target for osteoporosis. We identified a quinoxaline moiety as a new small-molecule inhibitor of the LRP5/6-sclerostin interaction through pharmacophore-based virtual screening, docking simulations, and in vitro assays. Structure-activity relationship studies and binding mode hypotheses were used to optimize the scaffold and yield the compound BMD4503-2, which recovered the downregulated activity of the Wnt/β-catenin signaling pathway by competitive binding to the LRP5/6-sclerostin complex. Overall, this study showed that the optimized structure-based drug design was a promising approach for the development of small-molecule inhibitors of the LRP5/6-sclerostin interaction. A novel scaffold offered considerable insights into the structural basis for binding to LRP5/6 and disruption of the sclerostin-mediated inhibition of Wnt signaling.

Keywords

LRP5/6-sclerostin interaction; Osteoporosis; Structure-activity relationships; Virtual screening; Wnt/β-catenin signalling pathway.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125146
    LRP5/6-sclerostin相互作用抑制剂
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