title: Accidental interaction between PDZ domains and diclofenac revealed by NMR-assisted virtual screening.
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.
authors: Laboratory of Structural Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Furocho, Chikusa-ku, Nagoya 464-8601, Japan. tenno.takeshi@e.mbox.nagoya-u.ac.jp
authors: Takeshi
authors: T
authors: Tenno
authors: Natsuko
authors: N
authors: Goda
authors: Yoshitaka
authors: Y
authors: Umetsu
authors: Motonori
authors: M
authors: Ota
authors: Kengo
authors: K
authors: Kinoshita
authors: Hidekazu
authors: H
authors: Hiroaki
mesh_terms: D030562:Databases, Protein; D004008:Diclofenac / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D054731:PDZ Domains; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D011506:Proteins; D004008:Diclofenac
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