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Accidental Interaction between PDZ Domains and Diclofenac Revealed by NMR-Assisted Virtual Screening
Laboratory of Structural Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Furocho, Chikusa-ku, Nagoya 464-8601, Japan
Division of Structural Biology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan
Center for Nano Materials and Technology, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, Ishikawa 923-1292, Japan
Department of Complex Systems Science, Graduate School of Information Sciences, Nagoya University, Nagoya 464-8601, Japan
Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Miyagi 980-8597, Japan
The Structural Biology Research Center and Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Nagoya 464-8601, Japan
* Author to whom correspondence should be addressed.
Received: 27 June 2013; in revised form: 1 August 2013 / Accepted: 5 August 2013 / Published: 9 August 2013
Abstract: In silico approaches have become indispensable for drug discovery as well as drug repositioning and adverse effect prediction. We have developed the eF-seek program to predict protein–ligand interactions based on the surface structure of proteins using a clique search algorithm. We have also developed a special protein structure prediction pipeline and accumulated predicted 3D models in the Structural Atlas of the Human Genome (SAHG) database. Using this database, genome-wide prediction of non-peptide ligands for proteins in the human genome was performed, and a subset of predicted interactions including 14 PDZ domains was then confirmed by NMR titration. Surprisingly, diclofenac, a non-steroidal anti-inflammatory drug, was found to be a non-peptide PDZ domain ligand, which bound to 5 of 15 tested PDZ domains. The critical residues for the PDZ–diclofenac interaction were also determined. Pharmacological implications of the accidental PDZ–diclofenac interaction are further discussed.
Keywords: PDZ domains; protein–protein interaction inhibitor; non-steroidal anti-inflammatory drug; drug repositioning
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Tenno, T.; Goda, N.; Umetsu, Y.; Ota, M.; Kinoshita, K.; Hiroaki, H. Accidental Interaction between PDZ Domains and Diclofenac Revealed by NMR-Assisted Virtual Screening. Molecules 2013, 18, 9567-9581.
Tenno T, Goda N, Umetsu Y, Ota M, Kinoshita K, Hiroaki H. Accidental Interaction between PDZ Domains and Diclofenac Revealed by NMR-Assisted Virtual Screening. Molecules. 2013; 18(8):9567-9581.
Tenno, Takeshi; Goda, Natsuko; Umetsu, Yoshitaka; Ota, Motonori; Kinoshita, Kengo; Hiroaki, Hidekazu. 2013. "Accidental Interaction between PDZ Domains and Diclofenac Revealed by NMR-Assisted Virtual Screening." Molecules 18, no. 8: 9567-9581.