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A structure‐based strategy for discovery of small ligands binding to functionally unknown proteins: Combination of in silico screening and surface plasmon resonance measurements
Author(s) -
Yoshitani Naoei,
Satou Kazuhito,
Saito Kazuki,
Suzuki Sakura,
Hatanaka Hideki,
Seki Motoaki,
Shinozaki Kazuo,
Hirota Hiroshi,
Yokoyama Shigeyuki
Publication year - 2005
Publication title -
proteomics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.26
H-Index - 167
eISSN - 1615-9861
pISSN - 1615-9853
DOI - 10.1002/pmic.200401032
Subject(s) - in silico , surface plasmon resonance , computational biology , drug discovery , rational design , dissociation constant , protein–protein interaction , ligand (biochemistry) , function (biology) , chemistry , affinities , biology , biochemistry , nanotechnology , materials science , receptor , genetics , nanoparticle , gene
In the postgenomic era, many researchers and organizations have been engaged in structural and functional analyses of proteins. As a part of these efforts, searching for small organic compounds that bind specifically to target proteins is quite important. In this study, we have developed a rational strategy for ligand discovery based on the three‐dimensional structures of target proteins, which were elucidated by X‐ray crystallography and nuclear magnetic resonance spectroscopy. The strategy has three features: (i) rapid selection of candidate compounds by in silico screening, (ii) automated preparation of sample solutions with robotics, and (iii) reliable evaluation of the candidates with surface plasmon resonance. Applying the strategy to a protein, At2g24940 from Arabidopsis thaliana , we discovered four small ligands out of a commercially available library of about 150 000 compounds. Although these compounds had only weak affinities to the target protein, with dissociation constants ranging from 68 to 120 µ M , they apparently possess common structural features. They would be leads for the development of specific inhibitors/drugs for At2g24940, and provide important clues toward elucidation of the protein function.