Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1

被引：30
|
作者：
Bach, Anders [2 ]
Stuhr-Hansen, Nicolai [2 ]
Thorsen, Thor S. [1 ]
Bork, Nicolai [3 ]
Moreira, Irina S. [4 ]
Frydenvang, Karla [2 ]
Padrah, Shahrokh [2 ]
Christensen, S. Brogger [2 ]
Madsen, Kenneth L. [1 ]
Weinstein, Harel [4 ]
Gether, Ulrik [1 ]
Stromgaard, Kristian [2 ]
机构：
[1] Univ Copenhagen, Panum Inst, Dept Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark
[2] Univ Copenhagen, Dept Med Chem, DK-2100 Copenhagen, Denmark
[3] Tech Univ Denmark, Riso Natl Lab Sustainable Energy, DK-4000 Roskilde, Denmark
[4] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA
来源：
ORGANIC & BIOMOLECULAR CHEMISTRY | 2010年 / 8卷 / 19期
基金：
美国国家卫生研究院;
关键词：
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.
引用
收藏
页码：4281 / 4288
页数：8
相关论文
共 50 条
  • [41] Functional interaction between the dopamine transporter and the synaptic PDZ domain-containing protein PICK1
    Torres, GE
    Yao, WD
    Caron, MG
    JOURNAL OF NEUROCHEMISTRY, 2001, 78 : 40 - 40
  • [42] HIGH-THROUGHPUT SCREENING IDENTIFIES SMALL-MOLECULE INHIBITORS OF THE CAL PDZ DOMAIN
    Cushing, P. R.
    Al Ayyoubi, S.
    Pellegrini, M.
    Mierke, D. F.
    Smithson, D.
    Guy, R. K.
    Madden, D. R.
    PEDIATRIC PULMONOLOGY, 2010, : 239 - 239
  • [43] Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction
    Edward Y. S. Lin
    Laura F. Silvian
    Douglas J. Marcotte
    Charles C. Banos
    Flora Jow
    Timothy R. Chan
    Robert M. Arduini
    Fang Qian
    Darren P. Baker
    Chris Bergeron
    Catherine A. Hession
    Richard L. Huganir
    Cassandra F. Borenstein
    Istvan Enyedy
    Jinming Zou
    Ellen Rohde
    Marion Wittmann
    Gnanasambandam Kumaravel
    Kenneth J. Rhodes
    Robert H. Scannevin
    Anthone W. Dunah
    Kevin M. Guckian
    Scientific Reports, 8
  • [44] Antiviral Activity of a Small-Molecule Inhibitor of Filovirus Infection
    Warren, Travis K.
    Warfield, Kelly L.
    Wells, Jay
    Enterlein, Sven
    Smith, Mark
    Ruthel, Gordon
    Yunus, Abdul S.
    Kinch, Michael S.
    Goldblatt, Michael
    Aman, M. Javad
    Bavari, Sina
    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2010, 54 (05) : 2152 - 2159
  • [45] Structure-Activity Relationships of Small Molecule Autotaxin Inhibitors with a Discrete Binding Mode
    Miller, Lisa M.
    Keune, Willem-Jan
    Castagna, Diana
    Young, Louise C.
    Duffy, Emma L.
    Potjewyd, Frances
    Salgado-Polo, Fernando
    Garcia, Paloma Engel
    Semaan, Dima
    Pritchard, John M.
    Perrakis, Anastassis
    Macdonad, Simon J. F.
    Jamieson, Craig
    Watson, Allan J. B.
    JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (02) : 722 - 748
  • [46] Identification and Structure-Activity Relationship Studies of Small-Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1
    Robaa, Dina
    Wagner, Tobias
    Luise, Chiara
    Carlino, Luca
    McMillan, Joel
    Flaig, Ralf
    Schuele, Roland
    Jung, Manfred
    Sippl, Wolfgang
    CHEMMEDCHEM, 2016, 11 (20) : 2327 - 2338
  • [47] Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction
    Lin, Edward Y. S.
    Silvian, Laura F.
    Marcotte, Douglas J.
    Banos, Charles C.
    Jow, Flora
    Chan, Timothy R.
    Arduini, Robert M.
    Qian, Fang
    Baker, Darren P.
    Bergeron, Chris
    Hession, Catherine A.
    Huganir, Richard L.
    Borenstein, Cassandra F.
    Enyedy, Istvan
    Zou, Jinming
    Rohde, Ellen
    Wittmann, Marion
    Kumaravel, Gnanasambandam
    Rhodes, Kenneth J.
    Scannevin, Robert H.
    Dunah, AnthoneW.
    Guckian, Kevin M.
    SCIENTIFIC REPORTS, 2018, 8
  • [48] Structure-activity relationship study of small-molecule inhibitor of Atg12-Atg3 protein-protein interaction
    Skach, Krystof
    Boserle, Jiri
    Nuta, Gal Chaim
    Brehova, Petra
    Bialik, Shani
    Carvalho, Silvia
    Kozer, Noga
    Barr, Haim
    Chaloupecka, Ema
    Kimchi, Adi
    Nencka, Radim
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2024, 112
  • [49] The crystal structure of the catalytic domain of tau tubulin kinase 2 in complex with a small-molecule inhibitor
    Marcotte, Douglas J.
    Spilker, Kerri A.
    Wen, Dingyi
    Hesson, Thomas
    Patterson, Thomas A.
    Kumar, P. Rajesh
    Chodaparambil, Jayanth, V
    ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, 2020, 76 : 103 - 108
  • [50] Identification of small-molecule compounds targeting the dishevelled PDZ domain by virtual screening and binding studies
    Choi, Jiwon
    Ma, SongLing
    Kim, Hyun-Yi
    Yun, Ji-Hye
    Heo, Jung-Nyoung
    Lee, Weontae
    Choi, Kang-Yell
    No, Kyoung Tai
    BIOORGANIC & MEDICINAL CHEMISTRY, 2016, 24 (15) : 3259 - 3266
12345