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Biol."],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:p>Studying the molecular mechanisms that underlie the relationship between drugs and the side effects they produce is critical for drug discovery and drug development. Currently, however, computational methods are still unavailable to assess drug\u2010protein interactions with the aim of globally inferring the contributions of various classes of proteins toward the etiology of side effects. In this work, we integrated data reflecting drug\u2010side effect relationships, drug\u2010target relationships, and protein\u2010protein interactions to develop a novel network\u2010based probabilistic model, <jats:italic>SidePro<\/jats:italic>, to evaluate the contributions of proteins toward the etiology of side effects. For a given side effect, the method applies an expectation\u2010\u2010\u2010maximization algorithm and a diffusion kernel\u2010based approach to estimate each protein\u2019s contribution. We applied this method to a wide range of side effects and validated the results using cross\u2010validation and records from the Side Effect Resource database. We also studied a specific side effect, nephrotoxicity, which is known to be associated with the irrational use of the Chinese herbal compound triptolide, a diterpenoid epoxide in the Thunder of God Vine, <jats:italic>Tripterygium wilfordii (Lei\u2010Gong\u2010Teng)<\/jats:italic>. Using triptolide as an example, we scored the target proteins of triptolide using our model and investigated the high\u2010scoring proteins and their related biological processes. The results demonstrated that our model could differentiate between the potential side effect targets and therapeutic targets of triptolide. Overall, the proposed model could accurately pinpoint the molecular mechanisms of drug side effects, thus making contribution to safe and effective drug development.<\/jats:p>","DOI":"10.1007\/s40484-015-0051-0","type":"journal-article","created":{"date-parts":[[2015,11,6]],"date-time":"2015-11-06T17:15:15Z","timestamp":1446830115000},"page":"124-134","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Network\u2010based method to infer the contributions of proteins to the etiology of drug side effects"],"prefix":"10.1002","volume":"3","author":[{"given":"Rui","family":"Li","sequence":"first","affiliation":[{"name":"<!--1--> MOE Key Laboratory of Bioinformatics and Bioinformatics Division TNLIST Department of Automation Tsinghua University Beijing 100084 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"<!--1--> MOE Key Laboratory of Bioinformatics and Bioinformatics Division TNLIST Department of Automation Tsinghua University Beijing 100084 China"},{"name":"<!--2--> Program in Computational Biology and Bioinformatics University of Southern California Los Angeles CA 90089 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shao","family":"Li","sequence":"additional","affiliation":[{"name":"<!--1--> MOE Key Laboratory of Bioinformatics and Bioinformatics Division TNLIST Department of Automation Tsinghua University Beijing 100084 China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,11]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/ci800344p"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.114"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1432"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2008.11.009"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.2217\/14622416.7.6.889"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.11.137"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1720"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep01543"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011764"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/456747"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102105\u201011\u2010S11\u2010S6"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/1752\u20100509\u20105\u2010S1\u2010S10"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1039\/c3mb70507b"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm801546k"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102105\u201012\u2010S2\u2010S2"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012063"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1089\/cmb.2010.0255"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201200337"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/ci2005548"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102164\u201012\u2010S5\u2010S11"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts383"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2013.10"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11159"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012063"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2009.98"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0140\u20106736(93)92984\u20102"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.2174\/0929867311320220006"},{"key":"e_1_2_7_29_2","first-page":"124","article-title":"Herbal treatments of glomerulonephritis and chronic renal failure: Review and recommendations for research","volume":"3","author":"Nowack R.","year":"2011","journal-title":"J. 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