PROTEIN-PROTEIN INTERACTIONS;
GLUTAMATE-RECEPTOR SUBUNIT-2;
LONG-TERM DEPRESSION;
KINASE-C-ALPHA;
AMPA RECEPTORS;
DRUG DESIGN;
HIPPOCAMPAL-NEURONS;
MEMBRANE CURVATURE;
ANALOG SYNTHESIS;
RATIONAL DESIGN;
D O I:
10.1039/c0ob00025f
中图分类号:
O62 [有机化学];
学科分类号:
070303 ;
081704 ;
摘要:
Recently, we described the first small-molecule inhibitor, (E)-ethyl 2-cyano-3-(3,4-dichlorophenyl)acryloylcarbamate (1), of the PDZ domain of protein interacting with C alpha-kinase 1 (PICK1), a potential drug target against brain ischemia, pain and cocaine addiction. Herein, we explore structure-activity relationships of 1 by introducing subtle modifications of the acryloylcarbamate scaffold and variations of the substituents on this scaffold. The configuration around the double bond of 1 and analogues was settled by a combination of X-ray crystallography, NMR and density functional theory calculations. Thereby, docking studies were used to correlate biological affinities with structural considerations for ligand-protein interactions. The most potent analogue obtained in this study showed an improvement in affinity compared to 1 and is currently a lead in further studies of PICK! inhibition.
机构:
Zhejiang Univ, Sch Med, Inst Neurosci, Dept Neurobiol, Hangzhou 310058, Zhejiang, Peoples R ChinaHong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China
Shao, Xin
Zhu, Lijun
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机构:
Zhejiang Univ, Sch Med, Inst Neurosci, Dept Neurobiol, Hangzhou 310058, Zhejiang, Peoples R ChinaHong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China
Zhu, Lijun
Wang, Yubin
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机构:
Zhejiang Univ, Sch Med, Inst Neurosci, Dept Neurobiol, Hangzhou 310058, Zhejiang, Peoples R ChinaHong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China
Wang, Yubin
Lu, Yuting
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机构:
Zhejiang Univ, Sch Med, Inst Neurosci, Dept Neurobiol, Hangzhou 310058, Zhejiang, Peoples R ChinaHong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China
Lu, Yuting
Wang, Wenhai
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机构:
Zhejiang Univ, ZJU ENS Joint Lab Med Chem, Hangzhou 310058, Zhejiang, Peoples R ChinaHong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China
Wang, Wenhai
Zhu, Jia
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机构:
Zhejiang Univ, Sch Med, Inst Neurosci, Dept Neurobiol, Hangzhou 310058, Zhejiang, Peoples R ChinaHong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China
Zhu, Jia
Shen, Ying
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机构:
Zhejiang Univ, Sch Med, Inst Neurosci, Dept Neurobiol, Hangzhou 310058, Zhejiang, Peoples R ChinaHong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China
Shen, Ying
Xia, Jun
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机构:
Hong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R ChinaHong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China
Xia, Jun
Luo, Jianhong
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机构:
Zhejiang Univ, Sch Med, Inst Neurosci, Dept Neurobiol, Hangzhou 310058, Zhejiang, Peoples R ChinaHong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China
机构:
St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USASt Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
Grandy, David
Shan, Jufang
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机构:
St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
Univ Tennessee, Hlth Sci Ctr, Interdisciplinary Grad Program, Memphis, TN 38163 USASt Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
Shan, Jufang
Zhang, Xinxin
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机构:
St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USASt Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
Zhang, Xinxin
Rao, Sujata
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机构:
Childrens Hosp Res Fdn, Dept Ophthalmol, Cincinnati, OH 45229 USA
Childrens Hosp Res Fdn, Div Dev Biol, Cincinnati, OH 45229 USASt Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
Rao, Sujata
Akunuru, Shailaja
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机构:
Childrens Hosp Res Fdn, Dept Ophthalmol, Cincinnati, OH 45229 USA
Childrens Hosp Res Fdn, Div Dev Biol, Cincinnati, OH 45229 USASt Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
Akunuru, Shailaja
Li, Hongyan
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机构:
Univ Paris 06, Dev Biol Lab, CNRS, UMR 7622, F-75005 Paris, FranceSt Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
机构:
Childrens Hosp Res Fdn, Dept Ophthalmol, Cincinnati, OH 45229 USA
Childrens Hosp Res Fdn, Div Dev Biol, Cincinnati, OH 45229 USASt Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
Lang, Richard A.
Shi, De-Li
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机构:
Univ Paris 06, Dev Biol Lab, CNRS, UMR 7622, F-75005 Paris, FranceSt Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
Shi, De-Li
Zheng, Jie J.
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机构:
St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
Univ Tennessee, Hlth Sci Ctr, Dept Mol Sci, Memphis, TN 38163 USASt Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA