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Exploration of system structure becomes important to reduce the complexity of the design problem.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this paper, we deduced a mathematical model which can simplify the serial structure and parallel structure of biological pathway for synergy evaluation of drug combinations. We demonstrated in steady state the sign of the synergism assessment factor derivative of the original system can be predicted by the sign of its simplified system. In addition, we analyzed the influence of feedback structure on survival ratio of the serial structure. We provided a sufficient condition under which the combination effect could be maintained. Furthermore, we applied our method to find three synergistic drug combinations on tumor necrosis factor \u03b1-induced NF\u03baB pathway and subsequently verified by the cell experiment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identified several structural properties underlying the Bliss independence criterion, and developed a systematic simplification framework for drug combiation desgin by combining simulation and system reaction network topology analysis. We hope that this work can provide insights to tackle the challenging problem of assessment of combinational drug therapy effect in a large scale signaling pathway. And hopefully in the future our method could be expanded to more general criteria.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1752-0509-4-50","type":"journal-article","created":{"date-parts":[[2010,4,27]],"date-time":"2010-04-27T06:14:00Z","timestamp":1272348840000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["A formal model for analyzing drug combination effects and its application in TNF-\u03b1-induced NF\u03baB pathway"],"prefix":"10.1186","volume":"4","author":[{"given":"Han","family":"Yan","sequence":"first","affiliation":[]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[]},{"given":"Shao","family":"Li","sequence":"additional","affiliation":[]},{"given":"Qianchuan","family":"Zhao","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2010,4,25]]},"reference":[{"key":"439_CR1","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1038\/nchembio817","volume":"2","author":"JB Fitzgerald","year":"2006","unstructured":"Fitzgerald JB, Schoeberl B, Nielsen UB, Sorger PK: Systems biology and combination therapy in the quest for clinical efficacy. 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