An integrative in silico approach for discovering candidates for drug-targetable protein-protein interactions in interactome data.
BACKGROUND
Protein-protein interactions (PPIs) are challenging but attractive targets for small chemical drugs. Whole PPIs, called the 'interactome', have been emerged in several organisms, including human, based on the recent development of high-throughput screening (HTS) technologies. Individual PPIs have been targeted by small drug-like chemicals (SDCs), however, interactome data have not been fully utilized for exploring drug targets due to the lack of comprehensive methodology for utilizing these data. Here we propose an integrative in silico approach for discovering candidates for drug-targetable PPIs in interactome data.


RESULTS
Our novel in silico screening system comprises three independent assessment procedures: i) detection of protein domains responsible for PPIs, ii) finding SDC-binding pockets on protein surfaces, and iii) evaluating similarities in the assignment of Gene Ontology (GO) terms between specific partner proteins. We discovered six candidates for drug-targetable PPIs by applying our in silico approach to original human PPI data composed of 770 binary interactions produced by our HTS yeast two-hybrid (HTS-Y2H) assays. Among them, we further examined two candidates, RXRA/NRIP1 and CDK2/CDKN1A, with respect to their biological roles, PPI network around each candidate, and tertiary structures of the interacting domains.


CONCLUSIONS
An integrative in silico approach for discovering candidates for drug-targetable PPIs was applied to original human PPIs data. The system excludes false positive interactions and selects reliable PPIs as drug targets. Its effectiveness was demonstrated by the discovery of the six promising candidate target PPIs. Inhibition or stabilization of the two interactions may have potential therapeutic effects against human diseases.
Sugaya
Nobuyoshi
N
PharmaDesign, Inc,, 2-19-8 Hatchobori, Chuo-ku, Tokyo, 104-0032, Japan. sugaya@pharmadesign.co.jp
Ikeda
Kazuyoshi
K
Tashiro
Toshiyuki
T
Takeda
Shizu
S
Otomo
Jun
J
Ishida
Yoshiko
Y
Shiratori
Akiko
A
Toyoda
Atsushi
A
Noguchi
Hideki
H
Takeda
Tadayuki
T
Kuhara
Satoru
S
Sakaki
Yoshiyuki
Y
Iwayanagi
Takao
T
D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D025941:Protein Interaction Mapping / Q000379:methods*; D017433:Protein Structure, Secondary / Q000502:physiology; D013678:Technology, Pharmaceutical / Q000379:methods
D004364:Pharmaceutical Preparations
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