Cited 7 times in
In silico discovery of quinoxaline derivatives as novel LRP5/6-sclerostin interaction inhibitors
DC Field | Value | Language |
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dc.contributor.author | 임승길 | - |
dc.date.accessioned | 2018-10-11T08:58:26Z | - |
dc.date.available | 2018-10-11T08:58:26Z | - |
dc.date.issued | 2018 | - |
dc.identifier.issn | 0960-894X | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/163516 | - |
dc.description.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. | - |
dc.description.statementOfResponsibility | restriction | - |
dc.language | English | - |
dc.publisher | Pergamon Press | - |
dc.relation.isPartOf | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.rights | https://creativecommons.org/licenses/by-nc-nd/2.0/kr/ | - |
dc.subject.MESH | Bone Morphogenetic Proteins/antagonists & inhibitors* | - |
dc.subject.MESH | Bone Morphogenetic Proteins/chemistry | - |
dc.subject.MESH | Dose-Response Relationship, Drug | - |
dc.subject.MESH | Drug Discovery* | - |
dc.subject.MESH | Genetic Markers | - |
dc.subject.MESH | Humans | - |
dc.subject.MESH | Low Density Lipoprotein Receptor-Related Protein-5/antagonists & inhibitors* | - |
dc.subject.MESH | Low Density Lipoprotein Receptor-Related Protein-5/chemistry | - |
dc.subject.MESH | Molecular Docking Simulation* | - |
dc.subject.MESH | Molecular Structure | - |
dc.subject.MESH | Quinoxalines/chemical synthesis | - |
dc.subject.MESH | Quinoxalines/chemistry | - |
dc.subject.MESH | Quinoxalines/pharmacology* | - |
dc.subject.MESH | Structure-Activity Relationship | - |
dc.subject.MESH | Wnt Signaling Pathway/drug effects | - |
dc.title | In silico discovery of quinoxaline derivatives as novel LRP5/6-sclerostin interaction inhibitors | - |
dc.type | Article | - |
dc.contributor.college | College of Medicine | - |
dc.contributor.department | Dept. of Internal Medicine | - |
dc.contributor.googleauthor | Jiwon Choi | - |
dc.contributor.googleauthor | Kyungro Lee | - |
dc.contributor.googleauthor | Myeongmo Kang | - |
dc.contributor.googleauthor | Sung-Kil Lim | - |
dc.contributor.googleauthor | Kyoung Tai No | - |
dc.identifier.doi | 10.1016/j.bmcl.2018.01.050 | - |
dc.contributor.localId | A03375 | - |
dc.relation.journalcode | J00326 | - |
dc.identifier.eissn | 1464-3405 | - |
dc.identifier.pmid | 29486968 | - |
dc.identifier.url | https://www.sciencedirect.com/science/article/pii/S0960894X18300581 | - |
dc.subject.keyword | LRP5/6-sclerostin interaction | - |
dc.subject.keyword | Osteoporosis | - |
dc.subject.keyword | Structure-activity relationships | - |
dc.subject.keyword | Virtual screening | - |
dc.subject.keyword | Wnt/β-catenin signalling pathway | - |
dc.contributor.alternativeName | Lim, Sung Kil | - |
dc.contributor.affiliatedAuthor | Lim, Sung Kil | - |
dc.citation.volume | 28 | - |
dc.citation.number | 6 | - |
dc.citation.startPage | 1116 | - |
dc.citation.endPage | 1121 | - |
dc.identifier.bibliographicCitation | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, Vol.28(6) : 1116-1121, 2018 | - |
dc.identifier.rimsid | 60463 | - |
dc.type.rims | ART | - |
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