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

Jiwon Choi, Kyungro Lee, Myeongmo Kang, Sungkil Lim, Kyoung Tai No

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1116-1121
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number6
DOIs
Publication statusPublished - 2018 Apr 1

Fingerprint

Catenins
Quinoxalines
Wnt Signaling Pathway
Computer Simulation
Wnt Receptors
Derivatives
Competitive Binding
Drug Design
Structure-Activity Relationship
Scaffolds
Osteoporosis
Homeostasis
Down-Regulation
Bone and Bones
Molecules
Assays
Screening
Bone
Therapeutics
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

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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.",
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In silico discovery of quinoxaline derivatives as novel LRP5/6-sclerostin interaction inhibitors. / Choi, Jiwon; Lee, Kyungro; Kang, Myeongmo; Lim, Sungkil; No, Kyoung Tai.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 28, No. 6, 01.04.2018, p. 1116-1121.

Research output: Contribution to journalArticle

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AU - No, Kyoung Tai

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