title: Rule-based multi-scale simulation for drug effect pathway analysis.
abstract: BACKGROUND
  Biological systems are robust and complex to maintain stable phenotypes under various conditions. In these systems, drugs reported the limited efficacy and unexpected side-effects. To remedy this situation, many pharmaceutical laboratories have begun to research combination drugs and some of them have shown successful clinical results. Complementary action of multiple compounds could increase efficacy as well as reduce side-effects through pharmacological interactions. However, experimental approach requires vast cost of preclinical experiments and tests as the number of possible combinations of compound dosages increases exponentially. Computer model-based experiments have been emerging as one of the most promising solutions to cope with such complexity. Though there have been many efforts to model specific molecular pathways using qualitative and quantitative formalisms, they suffer from unexpected results caused by distant interactions beyond their localized models.
  
  
  RESULTS
  In this work, we propose a rule-based multi-scale modelling platform. We have tested this platform with Type 2 diabetes (T2D) model, which involves the malfunction of numerous organs such as pancreas, circulation system, liver, and adipocyte. We have extracted T2D-related 190 rules by manual curation from literature, pathway databases and converting from different types of existing models. We have simulated twenty-two T2D drugs. The results of our simulation show drug effect pathways of T2D drugs and whether combination drugs have efficacy or not and how combination drugs work on the multi-scale model.
  
  
  CONCLUSIONS
  We believe that our simulation would help to understand drug mechanism for the drug development and provide a new way to effectively apply existing drugs for new target. It also would give insight for identifying effective combination drugs.
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon, South Korea.
authors.forename: Woochang
authors.initials: W
authors.lastname: Hwang
authors.forename: Yongdeuk
authors.initials: Y
authors.lastname: Hwang
authors.forename: Sunjae
authors.initials: S
authors.lastname: Lee
authors.forename: Doheon
authors.initials: D
authors.lastname: Lee
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000592:standards*; D000465:Algorithms; D003198:Computer Simulation / Q000145:classification / Q000592:standards; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics; D004338:Drug Combinations; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects; D010641:Phenotype
chemical_list: D004338:Drug Combinations; D007328:Insulin