Cross-reactivity virtual profiling of the human kinome by X-react(KIN): a chemical systems biology approach

TitleCross-reactivity virtual profiling of the human kinome by X-react(KIN): a chemical systems biology approach
Publication TypeJournal Article
Year of Publication2010
AuthorsBrylinski M, Skolnick J
JournalMol Pharm
Volume7
Issue6
Pagination2324-33
Date Published2010 Dec 6
ISSN1543-8392
KeywordsAdenosine Triphosphate, Artificial Intelligence, Binding Sites, High-Throughput Screening Assays, Humans, Internet, Models, Statistical, Protein Kinase Inhibitors, Protein Kinases, Proteomics, Structure-Activity Relationship, Substrate Specificity, Systems Biology
Abstract

Many drug candidates fail in clinical development due to their insufficient selectivity that may cause undesired side effects. Therefore, modern drug discovery is routinely supported by computational techniques, which can identify alternate molecular targets with a significant potential for cross-reactivity. In particular, the development of highly selective kinase inhibitors is complicated by the strong conservation of the ATP-binding site across the kinase family. In this paper, we describe X-React(KIN), a new machine learning approach that extends the modeling and virtual screening of individual protein kinases to a system level in order to construct a cross-reactivity virtual profile for the human kinome. To maximize the coverage of the kinome, X-React(KIN) relies solely on the predicted target structures and employs state-of-the-art modeling techniques. Benchmark tests carried out against available selectivity data from high-throughput kinase profiling experiments demonstrate that, for almost 70% of the inhibitors, their alternate molecular targets can be effectively identified in the human kinome with a high (>0.5) sensitivity at the expense of a relatively low false positive rate (<0.5). Furthermore, in a case study, we demonstrate how X-React(KIN) can support the development of selective inhibitors by optimizing the selection of kinase targets for small-scale counter-screen experiments. The constructed cross-reactivity profiles for the human kinome are freely available to the academic community at http://cssb.biology.gatech.edu/kinomelhm/ .

Alternate JournalMolecular Pharmaceutics
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