A probabilistic approach to identify putative drug targets in biochemical networks.
Network-based drug design holds great promise in clinical research as a way to overcome the limitations of traditional approaches in the development of drugs with high efficacy and low toxicity. This novel strategy aims to study how a biochemical network as a whole, rather than its individual components, responds to specific perturbations in different physiological conditions. Proteins exerting little control over normal cells and larger control over altered cells may be considered as good candidates for drug targets. The application of network-based drug design would greatly benefit from using an explicit computational model describing the dynamics of the system under investigation. However, creating a fully characterized kinetic model is not an easy task, even for relatively small networks, as it is still significantly hampered by the lack of data about kinetic mechanisms and parameters values. Here, we propose a Monte Carlo approach to identify the differences between flux control profiles of a metabolic network in different physiological states, when information about the kinetics of the system is partially or totally missing. Based on experimentally accessible information on metabolic phenotypes, we develop a novel method to determine probabilistic differences in the flux control coefficients between the two observable phenotypes. Knowledge of how differences in flux control are distributed among the different enzymatic steps is exploited to identify points of fragility in one of the phenotypes. Using a prototypical cancerous phenotype as an example, we demonstrate how our approach can assist researchers in developing compounds with high efficacy and low toxicity.
Doctoral Training Centre Integrative Systems Biology from Molecules to Life, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK. ettore.murabito@postgrad.manchester.ac.uk
Ettore
E
Murabito
Kieran
K
Smallbone
Jonathan
J
Swinton
Hans V
HV
Westerhoff
Ralf
R
Steuer
D002244:Carbon / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D015233:Models, Statistical; D009010:Monte Carlo Method; D009369:Neoplasms / Q000188:drug therapy; D010641:Phenotype
D002244:Carbon