Network-Based Target Selection For Multi-Targeted Therapy

Question

[miquelduranfrigola]

Hi all,

does any of you know of a method to select multiple targets that, if perturbed together, would result in a synergistic effect?

If so, what kind of networks would you use? Metabolic networks, protein-protein interaction networks, gene regulatory networks?

My plan is to choose different target profiles to test drug combinations or polypharmacological drugs.

Thanks in advance,

Miquel

Answer 1

[B. Arman Aksoy]

As far as I know, there is no such general method that will propose targets of which inhibition will result in synergistic effect, because:

• Most of these synergistic effects are context-specific (e.g. a synergistic combination in cell line A may not be synergistic in cell line B)
• The definition of synergistic might mean different things in different contexts depending on how you calculate it, dose of your compounds and the phenotype you are measuring
• To pick such candidates in a systematic manner, you need a computational model (that can capture inhibition and predict the phenotype of interest)

and all of these methods/decisions might differ from the experiment to experiment.

For general information on this topic, I would suggest you survey the "efficient experimental design" papers, e.g.

http://scholar.google.com/scholar?q=efficient+design+synergistic+drug

and then pick a computational model that best fits to your assumptions and do simulations on it... Or you can simply survey the literature for drug pairs that were previously shown to be synergistic in some context and limit your search space based on that.