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      Drug Discovery Using Chemical Systems Biology: Identification of the Protein-Ligand Binding Network To Explain the Side Effects of CETP Inhibitors

      1 , 2 , 3 , * , 1 , 3 , *

      PLoS Computational Biology

      Public Library of Science

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Systematic identification of protein-drug interaction networks is crucial to correlate complex modes of drug action to clinical indications. We introduce a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale and apply it to elucidating the molecular mechanisms associated with the adverse drug effects of Cholesteryl Ester Transfer Protein (CETP) inhibitors. CETP inhibitors are a new class of preventive therapies for the treatment of cardiovascular disease. However, clinical studies indicated that one CETP inhibitor, Torcetrapib, has deadly off-target effects as a result of hypertension, and hence it has been withdrawn from phase III clinical trials. We have identified a panel of off-targets for Torcetrapib and other CETP inhibitors from the human structural genome and map those targets to biological pathways via the literature. The predicted protein-ligand network is consistent with experimental results from multiple sources and reveals that the side-effect of CETP inhibitors is modulated through the combinatorial control of multiple interconnected pathways. Given that combinatorial control is a common phenomenon observed in many biological processes, our findings suggest that adverse drug effects might be minimized by fine-tuning multiple off-target interactions using single or multiple therapies. This work extends the scope of chemogenomics approaches and exemplifies the role that systems biology has in the future of drug discovery.

          Author Summary

          Both the cost to launch a new drug and the attrition rate during the late stage of the drug discovery and development process are increasing. Torcetrapib is a case in point, having been withdrawn from phase III clinical trials after 15 years of development and an estimated cost of US $800 M. Torcetrapib represents a new class of therapies for the treatment of cardiovascular disease; however, clinical studies indicated that Torcetrapib has deadly side-effects as a result of hypertension. To understand the origins of these adverse drug reactions from Torcetrapib and other related drugs undergoing clinical trials, we introduce a systematic strategy to identify off-targets in the human structural proteome and investigate the roles of these off-targets in impacting human physiology and pathology using biochemical pathway analysis. Our findings suggest that potential side-effects of a new drug can be identified at an early stage of the development cycle and be minimized by fine-tuning multiple off-target interactions. The hope is that this can reduce both the cost of drug development and the mortality rates during clinical trials.

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          Most cited references 111

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          Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.

           S Altschul (1997)
          The BLAST programs are widely used tools for searching protein and DNA databases for sequence similarities. For protein comparisons, a variety of definitional, algorithmic and statistical refinements described here permits the execution time of the BLAST programs to be decreased substantially while enhancing their sensitivity to weak similarities. A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original. In addition, a method is introduced for automatically combining statistically significant alignments produced by BLAST into a position-specific score matrix, and searching the database using this matrix. The resulting Position-Specific Iterated BLAST (PSI-BLAST) program runs at approximately the same speed per iteration as gapped BLAST, but in many cases is much more sensitive to weak but biologically relevant sequence similarities. PSI-BLAST is used to uncover several new and interesting members of the BRCT superfamily.
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            The Protein Data Bank.

            The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
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              Identification of common molecular subsequences.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                1553-734X
                1553-7358
                May 2009
                May 2009
                15 May 2009
                : 5
                : 5
                Affiliations
                [1 ]Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America
                [2 ]Torrey Pines High School, San Diego, California, United States of America
                [3 ]San Diego Supercomputer Center, University of California San Diego, La Jolla, California, United States of America
                National Cancer Institute, United States of America and Tel Aviv University, Israel
                Author notes

                Conceived and designed the experiments: Lei Xie PEB. Performed the experiments: Li Xie JL Lei Xie. Analyzed the data: Li Xie Lei Xie. Contributed reagents/materials/analysis tools: Lei Xie. Wrote the paper: Li Xie Lei Xie PEB.

                Article
                09-PLCB-RA-0078R2
                10.1371/journal.pcbi.1000387
                2676506
                19436720
                Xie et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 12
                Categories
                Research Article
                Biotechnology/Protein Chemistry and Proteomics
                Biotechnology/Small Molecule Chemistry
                Cardiovascular Disorders/Hypertension
                Computational Biology/Literature Analysis
                Computational Biology/Macromolecular Structure Analysis
                Computational Biology/Systems Biology
                Pharmacology/Adverse Reactions

                Quantitative & Systems biology

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