Optimized Method of G-Protein-Coupled Receptor Homology Modeling: Its Application to the Discovery of Novel CXCR7 Ligands
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- Yasushi Yoshikawa
- Drug Discovery Department, Research & Development Division, PharmaDesign Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo 104-0032, Japan
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- Shinya Oishi
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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- Tatsuhiko Kubo
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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- Noriko Tanahara
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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- Nobutaka Fujii
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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- Toshio Furuya
- Drug Discovery Department, Research & Development Division, PharmaDesign Inc., 2-19-8 Hatchobori, Chuo-ku, Tokyo 104-0032, Japan
書誌事項
- 公開日
- 2013-05-29
- 資源種別
- journal article
- DOI
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- 10.1021/jm400307y
- 公開者
- American Chemical Society (ACS)
この論文をさがす
説明
Homology modeling of G-protein-coupled seven-transmembrane receptors (GPCRs) remains a challenge despite the increasing number of released GPCR crystal structures. This challenge can be attributed to the low sequence identity and structural diversity of the ligand-binding pocket of GPCRs. We have developed an optimized GPCR structure modeling method based on multiple GPCR crystal structures. This method was designed to be applicable to distantly related receptors of known structural templates. CXC chemokine receptor (CXCR7) is a potential drug target for cancer chemotherapy. Homology modeling, docking, and virtual screening for CXCR7 were carried out using our method. The predicted docking poses of the known antagonists were different from the crystal structure of human CXCR4 with the small-molecule antagonist IT1t. Furthermore, 21 novel CXCR7 ligands with IC50 values of 1.29-11.4 μM with various scaffolds were identified by structure-based virtual screening.
収録刊行物
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- Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry 56 (11), 4236-4251, 2013-05-29
American Chemical Society (ACS)
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キーワード
- Models, Molecular
- Receptors, CXCR
- Receptors, CXCR4
- Sequence Homology, Amino Acid
- Protein Conformation
- Molecular Sequence Data
- CHO Cells
- Ligands
- High-Throughput Screening Assays
- Molecular Docking Simulation
- Small Molecule Libraries
- Radioligand Assay
- Structure-Activity Relationship
- Cricetulus
- Cricetinae
- Animals
- Humans
- Amino Acid Sequence
- Sequence Alignment
詳細情報 詳細情報について
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- CRID
- 1360004233223984128
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- ISSN
- 15204804
- 00222623
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- PubMed
- 23656360
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- 資料種別
- journal article
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- データソース種別
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- Crossref
- KAKEN
- OpenAIRE
