Chemical combination effects predict connectivity in biological systems
general idea
- study the effect of pathway connectivity on drug interactions (quantitatively measured as combined effect curve)
connectivity is a more general concept than interaction, as it includes the topology of the pathway in which the protein takes part
- a typical synergic effect in the combined drug response curve: (missing picture)
- the model of metabolic pathway probed: (missing picture)
main findings (understood)
pathway topology is the outstanding factor determining the shape of the combined effect curve
(assessed by systematic random perturbation of the kinetic parameters)- linear additive effect arise when two drugs target the same reaction
- epistatic effect arise when
two drug targets are serially connected in a linear pathway
the combined effect is even less effective if the serial pathway has a significant bypass
- or when two drugs act on different branches converging onto an AND gate
- synergic effects typically arise when drug targets act on different branches converging onto an OR gate
main findings (not understood)
the meaning of the response curve tagged Potentiation
- the effect of negative feedback in determining the curve shape
- why they chose as biochemical system the S. cer. sterol pathway, which has negative feedbacks, but not OR/AND branches
- the conclusion from studies on human cancer cells, and signaling pathways