title: Predicting and characterizing selective multiple drug treatments for metabolic diseases and cancer.
abstract: BACKGROUND
  In the field of drug discovery, assessing the potential of multidrug therapies is a difficult task because of the combinatorial complexity (both theoretical and experimental) and because of the requirements on the selectivity of the therapy. To cope with this problem, we have developed a novel method for the systematic in silico investigation of synergistic effects of currently available drugs on genome-scale metabolic networks.
  
  
  RESULTS
  The algorithm finds the optimal combination of drugs which guarantees the inhibition of an objective function, while minimizing the side effect on the other cellular processes. Two different applications are considered: finding drug synergisms for human metabolic diseases (like diabetes, obesity and hypertension) and finding antitumoral drug combinations with minimal side effect on the normal human cell. The results we obtain are consistent with some of the available therapeutic indications and predict new multiple drug treatments. A cluster analysis on all possible interactions among the currently available drugs indicates a limited variety on the metabolic targets for the approved drugs.
  
  
  CONCLUSIONS
  The in silico prediction of drug synergisms can represent an important tool for the repurposing of drugs in a realistic perspective which considers also the selectivity of the therapy. Moreover, for a more profitable exploitation of drug-drug interactions, we have shown that also experimental drugs which have a different mechanism of action can be reconsider as potential ingredients of new multicompound therapeutic indications. Needless to say the clues provided by a computational study like ours need in any case to be thoroughly evaluated experimentally.
authors.affiliation: Statistical and Biological Physics Department, SISSA-International School for Advanced Studies, Via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Facchetti
authors.forename: Mattia
authors.initials: M
authors.lastname: Zampieri
authors.forename: Claudio
authors.initials: C
authors.lastname: Altafini
mesh_terms: D000465:Algorithms; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003198:Computer Simulation; D015195:Drug Design; D004347:Drug Interactions; D004357:Drug Synergism; D004360:Drug Therapy, Computer-Assisted / Q000379:methods; D006801:Humans; D008659:Metabolic Diseases / Q000188:drug therapy* / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020543:Proteome