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Molecules 2013, 18(8), 9567-9581; doi:10.3390/molecules18089567
Article

Accidental Interaction between PDZ Domains and Diclofenac Revealed by NMR-Assisted Virtual Screening

1,2
,
1
,
2,3
,
4
,
5
 and
1,2,6,*
1 Laboratory of Structural Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Furocho, Chikusa-ku, Nagoya 464-8601, Japan 2 Division of Structural Biology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan 3 Center for Nano Materials and Technology, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, Ishikawa 923-1292, Japan 4 Department of Complex Systems Science, Graduate School of Information Sciences, Nagoya University, Nagoya 464-8601, Japan 5 Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Miyagi 980-8597, Japan 6 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 / Revised: 1 August 2013 / Accepted: 5 August 2013 / Published: 9 August 2013
(This article belongs to the Special Issue NMR of Proteins and Small Biomolecules)
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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 PDZ domains; protein–protein interaction inhibitor; non-steroidal anti-inflammatory drug; drug repositioning
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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.

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