A pipeline for testing drug mechanism of action and combination therapies: From microarray data to simulations via Linear-In-Flux-Expressions

Computational methods are becoming commonly used in many areas of medical research. Recently, the modeling of biological mechanisms associated with disease pathophysiology have benefited from approaches such as Quantitative Systems Pharmacology (briefly QSP) and Physiologically Based Pharmacokinetics (briefly PBPK). These methodologies show the potential to enhance, if not substitute animal models. The main reasons for this success are the high accuracy and low cost. Solid mathematical foundations of such methods, such as compartmental systems and flux balance analysis, provide a good base on which to build computational tools. However, there are many choices to be made in model design, that will have a large impact on how these methods perform as we scale up the network or perturb the system to uncover the mechanisms of action of new compounds or therapy combinations. A computational pipeline is presented here that starts with available-omic data and utilizes advanced mathematical simulations to inform the modeling of a biochemical system. Specific attention is devoted to creating a modular workflow, including the mathematical rigorous tools to represent complex chemical reactions, and modeling drug action in terms of its impact on multiple pathways. An application to optimizing combination therapy for tuberculosis shows the potential of the approach. •Computational pipeline describing integration of genetic data with metabolic pathways.•Simulation on metabolic networks provides insight into treatment mechanism of action.•Linear-In-Flux-Expressions offer a foundation for Quantitative Systems Pharmacology.