Example 2: Model approach for anti-inflamatory drugs

Problem: to assess efficacy of anti-inflammatory drugs and drug candidates.

Drug assessed: aspirin, celecoxib, diclofenac, naproxen, indomethacin, ibuprofen, vioxx, etc.

Motivation:

  • NSAIDs – popular anti-inflammatory drugs, more recently started to be used in cancer and even depression.
  • Main target – COX1,2.
  • “True measure” of efficacy of NSAID is dissociation and rate constants characterizing binding of the drug to COX-1 and COX-2.
  • “Apparent measure” of efficacy of NSAID is IC50 estimated on the basis of experiments with cell culture.
  • Values of dissociation and rate constants characterizing binding of the drug to COX-1 and COX-2 is difficult to measure.
  • Values of an IC50 measured in experiments with cell culture vary substantially be several order of magnitude depending on experimental conditions&nbsp.
Approach:
  • to develop model of inflammation in cell culture,
  • verify it on the basis of well known NSAIDs,
  • apply the model to calculate values of dissociation and rate constants characterizing binding of the drug to COX-1 and COX-2 on the basis of experimentally measured IC50 and experimental conditions.
ex2_iflamation_1.gif

Results 1: Model of inflammation in cell culture has been developed and verified against data available in public sources.
ex2_iflammation_2.jpg
Results 2: Using the model of inflammation we have developed Advisory Software Package (ASP) “COXulator”. This package calculates true kinetic parameters (dissociation and rate constants) of drug precursors on the basis of measured dose dependence and type of assay. This allows to exclude from further development those compounds which do not satisfy “specificity” and “binding time” requirements. Moreover, “COXulator” can be used to resolve reverse problem, i.e. to predict IC50 of the drug precursor on the basis of its known values of dissociation and rate constants and assay type.

Conclusions:

  • All data on operation of inflammatory pathways available in public sources have been integrated into kinetic model of inflammation in cell culture.
  • Software package “COXulator” based on the developed kinetic model of inflammation has been developed.
  • Using the package, the dissociation and rate constants of  multiple drug precursors have been calculated on the basis of measured dose dependence and type of assay.

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