Application of Sensitivity Analysis to Discover Potential Molecular Drug Targets

Abstract

Mathematical modeling of signaling pathways and regulatory networks has been supporting experimental research for some time now. Sensitivity analysis, aimed at finding model parameters whose changes yield significantly altered cellular responses, is an important part of modeling work. However, sensitivity methods are often directly transplanted from analysis of technical systems, and thus, they may not serve the purposes of analysis of biological systems. This paper presents a novel sensitivity analysis method that is particularly suited to the task of searching for potential molecular drug targets in signaling pathways. Using two sample models of pathways, p53/Mdm2 regulatory module and IFN-β-induced JAK/STAT signaling pathway, we show that the method leads to biologically relevant conclusions, identifying processes suitable for targeted pharmacological inhibition, represented by the reduction of kinetic parameter values. That, in turn, facilitates subsequent search for active drug components.

Pharmacodynamic model of PARP1 inhibition and global sensitivity analyses can lead to cancer biomarker discovery

“…Here, two related rate constants that direct protein synthesis and degradation were found to contribute to the most variability in model output, caspase activation. Recently, Kardynska et al, presented a novel sensitivity analysis utilizing a p53 network model without explicit apoptotic reaction rules and discovered similar sensitive parameters affecting transcription and translation rates as critical drug targets to modulate p53 induction of programmed cell death [52].…”

“…Here, two related rate constants that direct protein synthesis and degradation were found to contribute to the most variability in model output, caspase activation. Recently, Kardynska et al ., presented a novel sensitivity analysis utilizing a p53 network model without explicit apoptotic reaction rules and discovered similar sensitive parameters affecting transcription and translation rates as critical drug targets to modulate p53 induction of programmed cell death [52]. Importantly, for this study, we focused on the parameters affecting caspase activation and the role of PARP1 inhibition and we further evaluated biomarkers of PARP1 inhibitor sensitivity or resistance and/or prognostic factors.…”

Mathematical modeling of regulatory networks of intracellular processes – Aims and selected methods

“…2 Actual time response of a signaling pathway (grey dashed line) and misleading results of experiments with several time-point measurements (black crosses). providing information about any system output, including one representing hypothetical molecules or molecules whose levels cannot be measured for any reason (as long, as it is represented by a variable in the model); facilitating faster prototyping in synthetic biology [65] , thus pushing forward development of new biomaterials, biosensors and advancing medicine [22] ; indicating prospective molecular drug targets, suggested by a tailored sensitivity analysis (and the first step for subsequent molecular dynamics modeling that significantly reduces costs associated with new drugs development) (e.g., [21] , [62] ; see also a critical review by [111] ); supporting therapy planning and predicting long-term response to treatment and transient (sometimes counterintuitive) changes in this response [39] . …”

“…indicating prospective molecular drug targets, suggested by a tailored sensitivity analysis (and the first step for subsequent molecular dynamics modeling that significantly reduces costs associated with new drugs development) (e.g., [21] , [62] ; see also a critical review by [111] );…”

“…Over time, more sophisticated methods have been developed to aid the drug development process. A recent work presents a variance-based sensitivity analysis method that has been tailored to the search for drug molecular targets [62] . The proposed method allows studying the drug-induced changes in model responses resulting from the action of hypothetical drugs that successively target the processes described in the model and at the same time tackle the problem of heterogeneity of cellular responses to a drug in a cell population [40] , [88] .…”