Algebraic study of receptor-ligand systems: a dose-response analysis

TL;DR

This paper uses algebraic methods to analyze dose-response curves in receptor-ligand systems, especially cytokine receptors, deriving explicit formulas for key metrics like amplitude and EC50.

Contribution

It introduces an algebraic approach using Gr"obner bases to analytically study dose-response metrics for a broad class of receptor-ligand models, including cytokine receptors.

Findings

Derived explicit formulas for amplitude and EC50 in cytokine receptor models

Extended algebraic methods to sequential receptor-ligand systems with kinases

Provided analytical tools for understanding receptor-ligand dose-response behavior

Abstract

The study of a receptor-ligand system generally relies on the analysis of its dose-response (or concentration-effect) curve, which quantifies the relation between ligand concentration and the biological effect (or cellular response) induced when binding its specific cell surface receptor. Mathematical models of receptor-ligand systems have been developed to compute a dose-response curve under the assumption that the biological effect is proportional to the number of ligand-bound receptors. Given a dose-response curve, two quantities (or metrics) have been defined to characterise the properties of the ligand-receptor system under consideration: amplitude and potency (or half-maximal effective concentration, and denoted by EC$_{50}$). Both the amplitude and the EC$_{50}$ are key quantities commonly used in pharmaco-dynamic modelling, yet a comprehensive mathematical investigation of the behaviour of these two metrics is still outstanding; for a large (and important) family of receptors, called cytokine receptors, we still do not know how amplitude and EC$_{50}$ depend on receptor copy numbers. Here we make use of algebraic approaches (Gr\"obner basis) to study these metrics for a large class of receptor-ligand models, with a focus on cytokine receptors. In particular, we introduce a method, making use of two motivating examples based on the interleukin-7 (IL-7) receptor, to compute analytic expressions for the amplitude and the EC$_{50}$. We then extend the method to a wider class of receptor-ligand systems, sequential receptor-ligand systems with extrinsic kinase, and provide some examples.