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BibTeX
Method for comparing the structures of protein ligand-binding sites and application for predicting protein-drug interactions
Proteins, structure, function, and bioinformatics, 2008-07, Vol.72 (1), p.367-381
Minai, Ryoichi
Matsuo, Yo
Onuki, Hiroyuki
Hirota, Hiroshi
2008
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
Minai, Ryoichi
Matsuo, Yo
Onuki, Hiroyuki
Hirota, Hiroshi
Titel
Method for comparing the structures of protein ligand-binding sites and application for predicting protein-drug interactions
Ist Teil von
Proteins, structure, function, and bioinformatics, 2008-07, Vol.72 (1), p.367-381
Ort / Verlag
Hoboken: Wiley Subscription Services, Inc., A Wiley Company
Erscheinungsjahr
2008
Quelle
Wiley Online Library - AutoHoldings Journals
Beschreibungen/Notizen
Many drugs, even ones that are designed to act selectively on a target protein, bind unintended proteins. These unintended bindings can explain side effects or indicate additional mechanisms for a drug's medicinal properties. Structural similarity between binding sites is one of the reasons for binding to multiple targets. We developed a method for the structural alignment of atoms in the solvent‐accessible surface of proteins that uses similarities in the local atomic environment, and carried out all‐against‐all structural comparisons for 48,347 potential ligand‐binding regions from a nonredundant protein structure subset (nrPDB, provided by NCBI). The relationships between the similarity of ligand‐binding regions and the similarity of the global structures of the proteins containing the binding regions were examined. We found 10,403 known ligand‐binding region pairs whose structures were similar despite having different global folds. Of these, we detected 281 region pairs that had similar ligands with similar binding modes. These proteins are good examples of convergent evolution. In addition, we found a significant correlation between Z‐score of structural similarity and true positive rate of “active” entries in the PubChem BioAssay database. Moreover, we confirmed the interaction between ibuprofen and a new target, porcine pancreatic elastase, by NMR experiment. Finally, we used this method to predict new drug–target protein interactions. We obtained 540 predictions for 105 drugs (e.g., captopril, lovastatin, flurbiprofen, metyrapone, and salicylic acid), and calculated the binding affinities using AutoDock simulation. The results of these structural comparisons are available at http://www.tsurumi.yokohama‐cu.ac.jp/fold/database.html Proteins 2008. © 2008 Wiley‐Liss, Inc.
Sprache
Englisch
Identifikatoren
ISSN: 0887-3585
eISSN: 1097-0134
DOI: 10.1002/prot.21933
Titel-ID: cdi_proquest_miscellaneous_71637146
Format
–
Schlagworte
Algorithms
,
Binding Sites
,
Biochemistry - methods
,
Biological Assay
,
Ligands
,
local atomic environment
,
Magnetic Resonance Spectroscopy
,
Pharmaceutical Preparations - metabolism
,
Protein Structure, Secondary
,
protein surface
,
protein-ligand recognition
,
Proteins - chemistry
,
Proteins - metabolism
,
Reproducibility of Results
,
structural genomics
,
structure alignment
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