Quantitative and network pharmacology: A case study of rhein alleviating pathological progress of renal interstitial...

The current network pharmacology model focuses mainly on static and qualitative characterisation between drugs and targets or molecular pathway networks, but it does not reflect the multi-scale, dynamic and quantitative process of drug action.

In this study, we developed a new model known as quantitative and network pharmacology (QNP) to characterise the dynamic and quantitative interventions of drugs within a multi-scale biological network.

Firstly, we used a systems biology method to construct a molecule-cell dynamic network model to simulate the pathological processes of diseases. Secondly, according to the principles of enzymatic kinetics, we generated a multi-scale drug intervention model to simulate the intervention of drugs in multi-scale networks at different concentrations and pathological stages. Finally, we took rhein treatment of renal interstitial fibrosis (RIF) as an example to illustrate the QNP model.

We successfully constructed the a QNP model that includes both a multi-scale dynamic network disease model and drug intervention model. The QNP model accurately simulated the pathological process of RIF, and the simulation results were validated by a series of cell and animal experiments. Meanwhile, the QNP model demonstrated that rhein can delay the pathological process at the studied concentrations of 5 nM, 10 nM, and 20 nM, and can also exert a better therapeutic effect on fibrosis before the proliferation stage of RIF. Furthermore, through uncertainty and sensitivity analysis, we identified that FAK and Smad3 may be potential targets for RIF.

Our QNP model provides a molecular-cellular understanding of the pathological mechanisms of RIF, serving as a new approach and strategy for the construction of dynamic multi-scale network model of diseases and drug intervention.