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.
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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.