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

Authors
 Jiwon Choi  ;  Kyungro Lee  ;  Myeongmo Kang  ;  Sung-Kil Lim  ;  Kyoung Tai No 
Citation
 Bioorganic & Medicinal Chemistry Letters, Vol.28(6) : 1116-1121, 2018 
Journal Title
 Bioorganic & Medicinal Chemistry Letters 
ISSN
 0960-894X 
Issue Date
2018
MeSH
Bone Morphogenetic Proteins/antagonists & inhibitors* ; Bone Morphogenetic Proteins/chemistry ; Dose-Response Relationship, Drug ; Drug Discovery* ; Genetic Markers ; Humans ; Low Density Lipoprotein Receptor-Related Protein-5/antagonists & inhibitors* ; Low Density Lipoprotein Receptor-Related Protein-5/chemistry ; Molecular Docking Simulation* ; Molecular Structure ; Quinoxalines/chemical synthesis ; Quinoxalines/chemistry ; Quinoxalines/pharmacology* ; Structure-Activity Relationship ; Wnt Signaling Pathway/drug effects
Keywords
LRP5/6-sclerostin interaction ; Osteoporosis ; Structure-activity relationships ; Virtual screening ; Wnt/β-catenin signalling pathway
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.
DOI
10.1016/j.bmcl.2018.01.050
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
임승길(Lim, Sung Kil)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/163516
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