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.
Highlights
Protein–ligand docking, a virtual in silico screening approach, is an indispensable technology for drug discovery
We limited the number of the target protein–ligand pairs according to the following four issues: (1) the target protein should be readily expressed in an E. coli system; (2) the predicted ligands should be drug-like compounds; (3) the predicted ligands should possess different skeletal structures than their natural ligand counterparts; and (4) the predicted ligands should be able to inhibit any interaction of the target proteins
We have only showed that DIF and FLF can bind to many of these PDZ domains; we did not examine whether DIF or FLF can inhibit the protein–protein interaction of the PDZ domain
Summary
Protein–ligand docking, a virtual in silico screening approach, is an indispensable technology for drug discovery. Many protein–ligand docking programs have been developed and are widely used [1,2,3] Both the commercial applications such as Glide [4], MOE/ASEDock [5], GOLD [6], FLOG [7], and FRED [8], and the academic applications, such as AutoDock [9] and Sievgene [10], are useful. EF-seek locates potential ligand binding sites in a protein structure using a clique search algorithm; if similar structures were deposited in the eF-site, the database searches for ligand binding sites [17,18] This tool was initially developed for annotating biochemical functions of proteins based on 3D protein structures. Well-known non-steroidal anti-inflammatory drugs (NSAIDs), accidentally bound to several (5 of 15 tested) PDZ domains
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