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 curveBR (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 pathwayBR the combined effect is even less effective if the serial pathway has a significant bypassBR

  • 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

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