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

Molecules

Takeshi Tenno⁴  Natsuko Goda⁴  Yoshitaka Umetsu³  Motonori Ota²  Kengo Kinoshita¹ 

[1] Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Miyagi 980-8597, Japan; E-Mail:;Department of Complex Systems Science, Graduate School of Information Sciences, Nagoya University, Nagoya 464-8601, Japan; E-Mail:;Division of Structural Biology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan; E-Mail:;Laboratory of Structural Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Furocho, Chikusa-ku, Nagoya 464-8601, Japan; E-Mails:

关键词: PDZ domains;    protein–protein interaction inhibitor;    non-steroidal anti-inflammatory drug;    drug repositioning;   

DOI  :  10.3390/molecules18089567

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.